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Abstract Background: Sickle cell crisis (SCC) remains a leading cause of emergency hospitalization and acute morbidity in patients with sickle cell disease (SCD). With improved survival in SCD, long-term complications such as cardiovascular disease are emerging as critical determinants of morbidity and mortality. While right-sided heart failure has been adequately explored in SCD, the specific contribution of the other cardiovascular conditions to in-hospital mortality during sickle cell crisis remains unclear. This study evaluates the independent impact of cardiovascular comorbidities on in-hospital mortality among adults hospitalized for SCC using a large, nationally representative database. Methods: This is a retrospective analysis involving adult hospitalizations (≥ 18 years old) for SCC in the United States (U.S) using 2016-2020 National Inpatient Sample (NIS). The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. ICD-10 codes used for SCC were: D570, D5721, D5741, D5743, D5745, D5781. Regarding cardiovascular co-morbidities, the study considered age, race (African American, Hispanic and Caucasian), dyslipidemia, hypertension, diabetes mellitus (both type 1 and type 2), systolic and diastolic heart failure, rheumatic valvular heart disease, atrial fibrillation/flutter, pulmonary hypertension, chronic coronary artery disease and ischemic stroke. Univariable Cox regression was performed to identify independent predictors associated with in-hospital mortality among patients admitted for SCC. All factors from the univariable analysis with p<0.20 were included in a multivariable Cox regression model. All the outcomes were adjusted for age, sex, and Charlson Comorbidity Index. P-value of ≤0.05 was used to determine statistical significance. Results: The current study analyzed 424,540 SCD patients admitted for SCC (mean age 32.4 years, 55.4% females), from 2016 to 2020. Each additional year of age beyond 18 was associated with a linearly increasing in-hospital mortality among study patients hospitalized for SCC. This observation was confirmed in both univariate (HR: 1.06, 95% CI: 1.05–1.07, p<0.001) and multivariate (HR: 1.05, 95% CI: 1.04–1.06, p<0.001) analyses. On univariable analysis of cardiovascular co-morbidities in patients admitted for SCC, a higher in-hospital mortality was conferred by: hypertension (HR: 2.40; 1.95 – 2.94, p <0.01) dyslipidemia (HR: 2.38; 1.54 – 3.65, p <0.01), diabetes mellitus (HR: 2.15; 1.51 – 3.04, p <0.01, systolic (HR: 5.20; 3.70 – 7.31, p <0.01) and diastolic heart failure (HR: 2.11; 1.44 – 3.08, p <0.01), atrial fibrillation/flutter (HR: 5.43; 4.04 – 7.32, p <0.01), pulmonary hypertension (HR: 2.34; 1.75 – 3.13, p <0.01) and ischemic stroke (HR: 5.75; 3.30 – 10.03, <0.01); a lower in-hospital mortality was associated with the African American race (HR: 0.43; 0.20 – 0.91, p = 0.027). In multivariable analysis of cardiovascular comorbidities that demonstrated nominal significance (p < 0.20) in univariable analysis, only the following remained significantly associated with in-hospital mortality: systolic heart failure (HR: 2.65; 1.77 – 3.98, p <0.01), atrial fibrillation/flutter (HR: 2.01; 1.41 – 2.8), p <0.01) and ischemic stroke (HR: 3.25; 1.85 – 5.71, p <0.01). Although not statistically significant in univariable analysis (p = 0.065), chronic coronary artery disease (CAD) emerged as a significant predictor of reduced in-hospital mortality in the multivariable analysis (HR: 0.52; 0.29–0.91, p = 0.021). Conclusions: Among adults hospitalized for sickle cell crises, select cardiovascular comorbidities, including systolic heart failure, atrial fibrillation/flutter, and ischemic stroke, were independently associated with significantly increased in-hospital mortality. Interestingly, CAD was linked to reduced mortality in adjusted models. This may be attributed to closer medical surveillance and management in patients with established CAD, along with the potential protective mechanism(s) in SCD that limit atherosclerotic progression — warranting further investigation

Abstract Background: Chemotherapy-induced cardiomyopathy (CIC) is a serious, and often irreversible complication in patients treated for hematologic malignancies. While therapies for hematologic malignancies continue to evolve, data on trends in in-hospital mortality among patients with concurrent hematologic malignancies and CIC are limited, and disparities by race and sex remain poorly characterized. This study examines national trends and demographic disparities in in-hospital mortality among patients with hematologic malignancies who developed CIC. Methods: The United States (U.S) National Inpatient Sample (NIS) from 2016 to 2020 was queried for patients diagnosed with malignant hematologic and lymphoid neoplasms who also developed CIC. Hematologic malignancies were identified using ICD-10 codes C81–C96, which include: C81 for Hodgkin lymphoma; C82–C86 for non-Hodgkin lymphomas; C88 for malignant immunoproliferative diseases (e.g., Waldenström macroglobulinemia, heavy chain disease); C90–C95 for leukemias of lymphoid, myeloid, monocytic, mixed, and unspecified cell types; and C96 for other or unspecified malignant neoplasms of lymphoid, hematopoietic, and related tissue. CIC was identified using ICD-10 code I42.7. The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. Multivariable regression analysis was performed to determine the odds of in-hospital mortality among patients with hematologic malignancies who developed CIC. Multivariable logistic regression followed by marginal effects was used to plot yearly trends in in-hospital mortality. All the outcomes were adjusted for gender, race, Charlson comorbidity index and hospital characteristics. P < 0.05 was used to determine statistical significance. The analysis was performed on STATA 16 software. Results: The study identified a total of 3,021,434 hospitalizations with hematologic malignancies, of which 11,115 (0.004%) had secondary diagnosis of CIC (mean age = 56.5 years, 52.5% males). Among 11,115 patients with hematologic malignancies who developed CIC, 740 (6.6%) patients died during the hospitalization. Multivariable logistic regression followed by marginal effects estimated a decrease in adjusted in-hospital mortality trend from 6.5% in 2016 to 4.3% in 2020. However, this decreasing mortality trend was not statistically significant after adjusting for gender, race, Charlson comorbidity index, and hospital characteristics (OR: 0.93; 95% CI: 0.83 – 1.05; trend p = 0.260). In-hospital mortality did not differ significantly between male vs. female patients with hematologic malignancies who developed CIC (OR: 1.02; 95% CI: 0.72 – 1.43; p = 0.921). There was no difference in overall in-hospital mortality of patients of White (reference) vs. Black (OR: 1.12; 95% CI: 0.72 – 1.76, p = 0.61) or Hispanic (OR: 0.63; 95% CI: 0.32 – 1.25, p = 0.18) race. However, males of the Black race demonstrated a lower in-hospital mortality vs. males of the White race (OR: 0.26; 95% CI: 0.09 – 0.77, p = 0.01). In addition, females of the Black race showed a higher in-hospital mortality vs. females of the White race (OR: 2.43; 95% CI: 1.40 – 4.25, p <0.01). Conclusions: In patients with hematologic malignancies who developed CIC, overall in-hospital mortality did not differ significantly by race alone. However, on sex-based stratification, Black males had lower in-hospital mortality compared to White males, while Black females had higher mortality than White females. These differences highlight potential race–sex disparities in outcomes that warrant further investigation.

Abstract Background: Chimeric Antigen Receptor T-cell therapy (CAR-T) has revolutionized the treatment landscape of hematological cancers, including B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL). However, the cardiac toxicity profile of this therapy is not well described in the literature. The majority of patients receiving CAR-T are older adults who may have pre-existing cardiovascular risk factors, received prior cardiotoxic therapy including anthracycline, alkylators, corticosteroids, proteosome inhibitors, radiation, autologous and allogeneic stem cell transplants. Due to a stricter patient selection for CAR-T clinical trials, cardiac adverse events (AEs) are infrequent. As the survival of patients with hematological malignancies continues to improve with advancements in therapy, it becomes critical to consider the cumulative cardiotoxic effects of these therapies. Therefore, a post-marketing pharmacovigilance analysis of the cardiac AEs reported to the FDA Adverse Event Reporting System (FAERS) for each CAR-T product was conducted to address this knowledge gap. Methods: All individual case safety reports of cardiac AEs listing any of the approved CAR-T therapies [Tisagenlecleucel (Tisa-cel), Axicabtagene ciloleucel (Axi-cel), Lisocabtagene maraleucel (Liso-cel), Brexucabtagene autoleucel (Brexu-cel), Idecabtagene vicleucel (Ide-cel), Ciltacabtagene autoleucel (Cilta-cel) and Obecabtagene autoleucel (Obe-cel)] as the suspected drug were identified from the FAERS database. Patient characteristics, including primary malignancy, age, sex, CAR-T product and AEs were described. Disproportionality analysis was performed using Reported Odds Ratio (ROR) to determine significant associations between CAR-T products and cardiac AEs. Results: There were 1362 cardiac AEs after CAR-T therapy reported in the FAERS database(602 with Axi-cel, 444 with Tisa-cel, 77 with Cilta-cel, 81 with Ide-cel, 128 with Brexu-cel, 30 with Liso-cel and 0 with Obe-cel).Of these, 57% were males, 8.6% occurred in patients <18 yrs, 35.4% in 18–64 yrs, and 32% in >65 yrs. There were 778 reports of arrythmias, 158 heart failures, 184 cardiac arrests, 43 pericardial AEs, 16 valvular AEs, 59 ischemic AEs, 10 cardiogenic shock, 8 myocarditis, and 106 other cardiac disorders (cardiac thrombus, cardiomegaly, cardiac rupture, orthostatic hypotension, hypertensive emergency/crisis etc.). In the entire cohort, males were more likely to develop pericardial (ROR=3.55, p=0.004) and valvular disorders (ROR=9.13, p=0.03), with females developing heart failure (ROR=1.61, p=0.005). Patients <18 years had a higher incidence of pericardial (ROR=3.44, p=0.006) and valvular disease (ROR=12.79, p<0.0001), while adults aged >65 had higher propensity of developing atrial tachyarrhythmias (ROR=2.74, p<0.0001), ventricular arrhythmias (ROR=3.04, p=0.001) and cardiogenic shock (ROR=8.38, p=0.05), and a trend towards higher risk of developing acute coronary syndrome (ACS) (ROR=1.79, p=0.06). For ischemic cardiac AEs, Brexu-cel was associated with increased risk of myocardial infarction (ROR=2.34, p=0.04), and Ide-cel was associated with elevated troponin levels (ROR=6.23, p=0.002). For functional cardiac AEs, Tisa-cel was associated with cardiac arrest (ROR=1.68, p=0.001), pericardial disorders (effusion, tamponade and pericarditis) (ROR=3.56, p<0.001), valvular disorders (ROR=55.97, p<0.0001), myocarditis (ROR=6.2, p=0.012) and heart failure (ROR=2.24, p<0.001). B-ALL was associated with higher odds of cardiac arrest (ROR=1.63, p=0.018). For conduction-related cardiac AEs, Brexu-cel had higher rates of brady-arrythmias (ROR=1.86, p=0.04), Cilta-cel had increased incidence of atrioventricular block (ROR=7.87, p=0.02), and tachy-arrhythmias (ROR=1.71, p=0.0001). Tisa-cel was associated with increased risk of any arrhythmias (ROR=1.68, p<0.001). Axi-cel was associated with higher odds of developing orthostatic hypotension (ROR=2.57, p=0.019). Conclusion: This post-marketing pharmacovigilance analysis highlights patterns of cardiac AEs following CAR-T therapy. Trends in AEs based on CAR-T product, age, and sex support the ongoing need for vigilance for these unique toxicities. As this study is limited by FAERS reporting bias, prospective studies to validate these associations and elucidate the underlying mechanisms are needed, incorporating prior systemic therapies and baseline characteristics of patients undergoing CAR-T therapy.

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

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels >60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required >2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was >60% and HbS was <40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to <40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.

Abstract Introduction: Patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) exhibit an elevated risk of developing other cancers (OC) relative to the general population. Historically, chemoimmunotherapy (CIT) represented the cornerstone of CLL/SLL management. A systematic review of clinical trials of CIT for CLL that included 28 studies reported 352/3297 (12.6%) patients developed OC (Csanadi 2022). The introduction of targeted agents beginning in the mid-2010's, including Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors, has shifted the standard of care toward these novel therapies. In this study, we determined the risk of OC in newly diagnosed CLL/SLL patients cared for at the US Department of Veteran Affairs (VA), The University of Texas MD Anderson Cancer Center, and Mayo Clinic in Rochester, MN. Methods: We identified patients with newly diagnosed CLL/SLL after 1/1/2016 using the VA Central Cancer Registry, MD Anderson, and the Mayo Clinic CLL Databases. The baseline clinical characteristics, CLL treatments, and the occurrence of OC were abstracted by electronic health record (EHR) review. Receipt of CLL directed therapy was categorized into a) CIT only; b) targeted therapy only; c) CIT and targeted therapy; and d) other (including monotherapy with monoclonal antibody therapy). The occurrence of OC was modeled using CLL treatment as a time-dependent variable. Prior and concurrent OC diagnosed within 3 months of CLL/SLL were excluded from analyses, to reduce ascertainment bias. Results: We identified 6844 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.6 years (interquartile range [IQR] 1.9-5.8). The median age at diagnosis of CLL/SLL was 71 years (range, 23 - 102); most patients were white (81%) and male (90%). Although many patients had missing values, among those with available information, IGHV genes were unmutated in 884 (51%), CLL FISH panel showed del17 in 213 (7%), del11q in 389 (13%), trisomy 12 in 674 (23%), and del13q in 1508 patients (50%). A total of 2344 patients received CLL directed therapy during follow-up: 278 (12%) received CIT only, 1809 (77%) received targeted therapy (+/- monoclonal antibody), only 99 (4%) received CIT and targeted therapy and 150 (6%) monoclonal antibody therapy only. Among patients treated with targeted therapies, 950 (50%) received ibrutinib, 381 (20%) received acalabrutinib, 164 (9%) received zanubrutinib, 4 (<1%) received orelabrutinib, 280 (15%) received venetoclax, and 3 (<1%) received sonrotoclax. Other treatments included combinations of a covalent BTKi (cBTKi) and BCL2i in 52 (3%) patients, among others. A total of 583 patients were diagnosed with OC during the study period. Types of OC observed included neoplasms of the prostate (n=129, 22%), lung (n=118, 20%), hematologic malignancies (n=91, 16%), gastrointestinal tract (n=68, 12%), melanoma (n=66, 11%), kidney and bladder (n=44, 8%), head and neck (n=19, 3%), and other/unknown (n=48, 8%). Estimated risk of occurrence of OC was 4.2% (95%CI 3.8-4.8%) at 24 months and 9.7% (95%CI 8.9-10.6%) at 60 months after a diagnosis of CLL/SLL. Multivariable analyses demonstrated that older age (HR: 1.013, 95%CI: 1.00-1.021), male sex (HR: 1.6, 95%CI: 1.1-2.3), and receipt of CLL directed therapy (HR: 1.4, 95%CI: 1.2-1.7) were associated with an increased risk of OC. When considering different types of CLL directed treatments, those who received CIT with or without targeted therapies had the highest risk of development of OC (HR: 1.6, 95%CI: 1.2-2.1). Risk of OC were also increased for those who received CIT only (HR: 1.41, 95%CI: 0.97-2.05) and those who received targeted treatments alone (HR: 1.27, 95%CI: 1.02-1.58). Conclusion: In this large dataset of newly diagnosed patients with CLL/SLL in the past ten years, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT with or without targeted therapy and was still elevated in those who received CIT only or targeted therapy only.

Abstract Background Chimeric antigen receptor T-cell (CAR-T) and bispecific antibody (BsAb) therapies are both effective for patients with relapsed/refractory (R/R) follicular lymphoma (FL), but differ in treatment schedules and associated “time toxicity,” or contact days spent physically interacting with the healthcare system. While contact days can be estimated from clinical trials, real-world data provides a more nuanced depiction of treatment-related time burden, which may guide treatment decision-making. The comparative time toxicity of CAR-T vs BsAb in R/R FL is not defined. Methods We conducted a multicenter retrospective study of adults with R/R grade 1-3A FL who received standard-of-care CAR-T (axi-cel, tisa-cel, liso-cel) or BsAb (mosunetuzumab, epcoritamab) in the third-line or later setting before Jan 1, 2025. Time toxicity was defined as outpatient or inpatient days with physical health care system contact, counting multiple visits on the same day as only one day. All days after treatment initiation were counted, regardless of disease progression, therapy completion, or relation to FL therapy. Median contact days over 1-year time horizon were compared, stratified by CAR-T vs BsAb, prior lines of therapy (LOT, 2 vs 3+), and time intervals (0-1, 1-3, 3-6, 6-9, and 9-12 months). Progression-free survival (PFS) and overall survival (OS) were calculated from day of CAR-T infusion or day 1, cycle 1 for BsAb. Cox regression and propensity matching (by age, ECOG, refractory to prior LOT, POD24) were used to assess predictors and survival associations with contact days. Results Among 209 patients from 15 U.S. academic centers, median age was 64, 37% were female, 61% received CAR-T (80% axi-cel, 7% liso-cel, 13% tisa-cel) and 39% BsAb (93% mosun, 7% epcor). Most had Grade 1-2 FL (72%), advanced stage (84%), and extranodal disease (51%). Median prior LOT was 3 (range 2-15), 41% were refractory to prior LOT, and 52% had POD24. Median number of BsAb doses was 10 (range 1-36). Patients receiving BsAb were significantly older (p<.01) and had higher CIRS comorbidity scores (p<.02) in both 2 and 3+ prior LOT cohorts, and had higher ECOG scores (p=.01) and were less likely to be refractory to prior LOT (p=.029) in 3+ LOT cohort. There were no differences in POD24 rates between CAR-T and BsAb. Median PFS for the entire cohort was 3.6 yrs; median OS was not reached. In the 2 prior LOT cohort (N=75), 60% received CAR-T and 40% BsAb. With median follow-up of 1.5 years, median PFS was not reached for CAR-T and 1.6 yrs for BsAb (p<.0001). In the 3+ prior LOT cohort (N=134), 62% received CAR-T and 38% BsAb. With median follow-up of 2 yrs, median PFS was 3.6 yrs for CAR-T and 1.6 yrs for BsAb (p=.0044). In propensity matched analysis, PFS was shorter for BsAb in both 2 LOT (HR 9.0, 95% CI 1.14-71.04, p=.037) and 3+ LOT (HR 3.25, 95% CI 1.06-9.97, p=.039) cohorts as compared to CAR-T. There were no significant differences in OS between CAR-T and BsAb. Median contact days were significantly higher for CAR-T vs BsAb in the 0-1 month interval: 19 vs 8 days in 2 LOT (p<.0001) and 18 vs 7 days in 3+ LOT (p<.0001) cohorts. There were no differences in contact days between CAR-T vs BsAb in subsequent time intervals. Over 1 year, CAR-T had significantly more time toxicity than BsAb: median 51 vs 36 contact days in 2 LOT (p<.0001) and 64 vs 38 days in 3L+ LOT (p<.0001) cohorts; these remained significant in the matched analysis. B symptoms (p=.04) and Grade ≥3 cytopenias (p=.007) were associated with higher contact days in 3+ LOT cohort in univariable analysis. Higher contact days were associated with inferior PFS (HR 1.01, 95% CI 1.00-1.02, p=.032) and OS (HR 1.01, 95% CI 1.00-1.02, p=.038) in 3+ LOT cohort regardless of treatment type. Discussion In this large real-world cohort of patients with R/R FL, CAR-T therapy resulted in better PFS but more time toxicity over the first year as compared to BsAb therapy. Excess time toxicity from CAR-T was driven by more contact days in the first month of treatment. This study provides benchmark data for counseling patients about expected time burden of CAR-T (51-64 days) and BsAb (36-38 days) over the first year of these therapies. Further, with superior PFS of CAR-T in this study and minimal impact of time toxicity on survival outcomes, these data can be used to better support shared decision-making in R/R FL by addressing patient preferences regarding both contact days as well as duration of disease control.

Abstract Introduction/Objective Mutations in KIT and PDGFRA drive the majority of gastrointestinal stromal tumors (GIST) and inform targeted therapy selection. While single-driver mutations are typical, a subset of cases harbors multiple KIT mutations, complicating clinical interpretation. This study investigated the frequency, distribution, and inferred hierarchy of primary and secondary KIT mutations using DNA-based sequencing in a large GIST cohort. Methods/Case Report We retrospectively reviewed 579 GIST cases that underwent DNA-based next-generation sequencing using a custom panel targeting all coding exons of KIT and PDGFRA. Tumor-rich formalin-fixed paraffin-embedded (FFPE) tissue was required. In double-mutant cases, the mutation with higher variant allele frequency (VAF) was presumed to be primary. Results Mutations in KIT or PDGFRA were detected in 482/579 cases (83.2%). Among KIT-mutant cases, 28 had two mutations and one had three. Secondary mutations frequently occurred in exons 13, 14, and 17 and were significantly more common in non-gastric tumors (p < 0.0001). Primary mutations most often involved exon 11. Conclusion VAF analysis enabled classification of mutation hierarchy in cases with multiple KIT mutations. The distinct anatomical and exon-specific distribution of primary vs. secondary mutations highlights their potential therapeutic implications and warrants further study.

Abstract INTRODUCTION Glioblastoma is the most common malignant adult brain tumor with poor prognosis, largely due to its heterogeneous landscape. The AI-RANO and RANO-RGP groups organized the BraTS-Pathology 2024 challenge, providing a publicly-available dataset and a benchmarking environment for AI models to automatically identify six clinically-relevant histopathologic sub-regions in H&E-stained whole slide images (WSIs). METHODS We reclassified the TCGA-GBM and TCGA-LGG data according to the WHO 2021 criteria and identified diagnostic WSIs of 188 glioblastoma (IDH-wt, CNS WHO Gr.4) patients. A well-defined annotation protocol was communicated to eight neuropathologists, across eight institutions, who created “ground truth” annotations for Cellular Tumor (CT), Geographic Necrosis, Cortical Infiltration, Pseudopalisading Necrosis (PN), Microvascular Proliferation, and Penetration into White Matter (PWM). Comprehensive WSI curation for elimination of artifactual content and follow up partitioning resulted in approximately 300,000 data samples/patches. FINDINGS Inter-observer variability assessment highlighted difficulties in establishing a “gold standard”. The least annotated sub-regions (PWM and PN) were the most challenging to the participating methods, whereas all methods achieved their highest accuracy in the most annotated sub-region (CT). The highest average performance across sub-regions was obtained by a foundation model-based method. However, this top-ranked solution achieved an F1 score of 0.51 (Accuracy=0.65, Sensitivity=0.56, Specificity=0.93). CONCLUSIONS Our findings suggest that achieving state-of-the-art performance, in automatically identifying clinically-relevant glioblastoma sub-regions, remains an unsolved research problem. Analysis of the ground-truth annotations underscores the critical need for more precisely defined and neuropathologically standardized annotation protocol. Current AI algorithms are facing difficulties in addressing glioblastoma’s heterogeneous histologic landscape in the absence of large, comprehensively, and consistently annotated data. Building upon these findings, and towards developing more accurate AI algorithms, the 2025 iteration of the BraTS-Path challenge is currently on-going by leveraging two million data samples, aiming to enhance our disease understanding and improve diagnostic accuracy, ultimately contributing to improved patient outcomes.