Citations

e18608 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) that is characterized by bone marrow fibrosis and inefficient hematopoiesis, leading to extramedullary hematopoiesis. Leukocytosis, a common disease manifestation and a minor criterion for the diagnosis of MF, has been associated with poorer clinical outcomes. This study evaluates the long term impact of leukocytosis on clinical outcomes at different time points in the real-world population of patients with MF. Methods: We conducted a retrospective cohort study using de-identified EHR data from the TriNetX Global Federated Health Research Network. Adults (≥18 years) with myelofibrosis were identified using ICD-10 and ICD-O-3 codes and stratified into leukocytosis (WBC ≥25.0 ×10³/µL; L+) and non-leukocytosis (L−) cohorts at the index diagnosis. Patients with prior or current hematopoietic stem cell transplantation were excluded. Cohorts were propensity score–matched 1:1 for demographics, comorbidities, and baseline laboratory values. Outcomes at 1, 3, and 5 years included all-cause mortality, pulmonary embolism, venous thromboembolism, and transformation to acute myeloid leukemia, with hazard ratios estimated using Cox proportional hazards models. Results: After matching, 13237 patients with MF were identified, of whom 52.12% were male, and 47.8% were female. The mean age in L+ and L- was 66.5 +/- 16.6 years and 68.1 +/- 15.5 years, respectively. The mean hemoglobin in L+ was 10.9+/- 2.8 g/dL, and in L- was 12.9+/- 2.3 g/dL. The mean platelet count in L+ was 303.4+/- 294.9 and in L- was 239.5+/- 151.4 ×10³/µL. HR for all-cause mortality in L+ when compared to L- at years 1, 3, and 5 were statistically significant at 4.079 (95% CI 3.691-4.508), 3.215 (95% CI 2.982-3.466), and 2.787 (95% CI 2.608-2.978), respectively, with log-rank p < 0.01. The HR for PE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.014 (95% CI 1.455-2.787), 1.883 (95% CI 1.451-2.787) and 1.659 (95% CI 1.318-2.088) with log-rank p<0.01. HR for VTE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.501 (95% CI 1.937-3 .229), 1.802 (95% CI 1.491-2.178), and 1.561 (95% CI 1.32-1.847) with log-rank p<0.01. Risk of transformation to AML in L+ when compared to L- at years 1, 3, and 5 was significant with HRs being 9.806 (95% CI 6.575-14.627), 8.823 (95% CI 6.334-12.29), 9.371 (95% CI 6.813-12.891) with log-rank p<0.01. Conclusions: In this large real-world, propensity-matched cohort, leukocytosis in myelofibrosis was associated with significantly higher risks of all-cause mortality, thromboembolic events, and transformation to acute myeloid leukemia across 1-, 3-, and 5-year time points. These findings underscore leukocytosis as a powerful adverse prognostic marker in MF and highlight the need for closer surveillance and risk-adapted therapeutic strategies in this high-risk population.

e18607 Background: Progression to myelofibrosis (MF) is associated with worse survival and influences treatment decisions, yet predictors of fibrotic progression in polycythemia vera (PV) and essential thrombocythemia (ET) remain poorly characterized. Methods: Patients with pathologically confirmed PV or ET were identified from a retrospective chart review. Demographics (age, sex, race, ethnicity), clinical features (thrombosis and bleeding history, performance status, symptom burden, organomegaly), bone marrow pathology (cellularity, trilineage hematopoiesis, megakaryocyte proliferation and atypia, fibrosis grade), molecular markers ( JAK2 , CALR , MPL , ASXL1 , EZH2 , TET2 , SRSF2 , IDH1/2 , SF3B1 , TP53 ), cytogenetics, laboratory values, and treatment history (phlebotomy, hydroxyurea, interferon, ruxolitinib) at first bone marrow biopsy were recorded. MF progression was defined as hematologist-confirmed transformation to MF. Kaplan-Meier analyses estimated median MF-free survival (MFS), defined as time to MF progression or death. Univariable followed by multivariable Cox proportional regression were performed to identify candidate MFS predictors. The proportional hazards assumption was assessed using Schoenfeld residuals. Hazard ratios (HR) with 95% confidence intervals (CI) were computed, with p<0.05 indicating statistical significance. Results: A total of 505 PV and 198 ET patients were identified. The majority were White (PV: 92%; ET: 86%). PV patients were predominantly male (54%) whereas ET patients were predominantly female (66%). MF progression occurred in 160 (32%) PV and 32 (16%) ET patients. Death was observed in 139 (28%) PV and 10 (5%) ET patients. Median MFS was 158.5 months (95% CI: 143.0-183.0) for PV and 308.0 months (95% CI: 175.0-NR) for ET. In PV, older age at diagnosis (HR 1.04; 95% CI: 1.02-1.07; p<0.001) and shorter time since PV or ET diagnosis to biopsy (HR 0.995; 95% CI: 0.990-0.999; p=0.048) independently predicted worse MFS. In ET, bone marrow hypercellularity (HR 5.67, 95% CI: 1.40-23.0, p=0.015) independently predicted worse MFS. Conclusions: PV patients demonstrated shorter MFS compared to ET. Older age at diagnosis in PV, whereas bone marrow hypercellularity in ET was significantly associated with fibrotic progression or death. Active surveillance of at-risk patients may facilitate early detection and timely treatment initiation. Disease Variable HR (95%CI) P-value PV Age at diagnosis 1.04 (1.02-1.07) <0.001 Time since PV or ET diagnosis to biopsy 0.995 (0.990-0.999) 0.048 ET Bone marrow hypercellularity 5.67 (1.40-23.0) 0.015

e18605 Background: Patients with myelofibrosis (MF), especially those with marked leukocytosis, face increased risk for thrombotic complications such as pulmonary embolism (PE) and venous thromboembolism (VTE). Hydroxyurea (HU) is often used to control blood counts. However, evidence for HU reducing thrombotic events in MF is limited, and contemporary real-world data on its impact in MF populations with significant leukocytosis remain sparse. Methods: We conducted a retrospective cohort study using the TriNetX research network. Adult patients with MF and leukocytosis (white blood cell count ≥25×10⁹/L) were identified. Patients with prior allogeneic hematopoietic stem cell transplantation were excluded. HU-exposed patients were compared with non-exposed patients using 1:1 propensity score matching. Matching criteria included age, sex, race, comorbidities, and baseline laboratory values when available. The study included 3,590 patients (1,795 per cohort). Primary outcomes were time to PE and VTE at 1, 3, and 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Results: In the propensity-matched cohort, HU exposure was not associated with a statistically significant reduction in thrombotic events. For PE, hazard ratios were numerically higher in the HU-exposed group at 1 year (1.5% vs 1.0%; HR 1.40, 95% CI 0.76–2.56; p=0.278) and 3 years (2.2% vs 1.8%; HR 1.29, 95% CI 0.80–2.08; p=0.289), with a modest increase observed at 5 years (2.8% vs 1.9%; HR 1.57, 95% CI 1.01–2.45; p=0.04). For VTE, no statistically significant differences were observed between HU-exposed and non-exposed patients at any time point (1 year: HR 0.95, 95% CI 0.63–1.44; p=0.821; 3 years: HR 0.97, 95% CI 0.69–1.36; p=0.85; 5 years: HR 1.14, 95% CI 0.84–1.57; p=0.40). Overall, PE and VTE event rates remained low and comparable between cohorts. Conclusions: In this large real-world cohort of patients with myelofibrosis and significant leukocytosis, hydroxyurea exposure was not associated with a statistically significant reduction in thrombotic events, including PE or VTE, over short- or long-term follow-up. Thrombotic event rates were low and generally comparable between hydroxyurea-exposed and non-exposed patients, with no consistent pattern suggesting a protective effect of cytoreductive therapy. Although a modest increase in PE risk was observed at 5 years, this finding was isolated and lacked a consistent temporal pattern, limiting its clinical interpretability. These findings suggest that the role of hydroxyurea in modifying thrombotic risk among MF patients with leukocytosis remains uncertain and highlight the need for individualized treatment decisions and further studies to better define its impact on thrombotic outcomes in this population.

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.

6525 Background: Venetoclax plus hypomethylating agent (Ven-HMA) is the standard treatment for unfit patients with newly diagnosed acute myeloid leukemia (ND-AML), with Ven typically administered for 28 days (d) per cycle (DiNardo NEJM 2020) . However, the optimal duration of Ven across risk groups remains unclear. We examined survival outcomes with Ven 7, 14, 21, and 28d in ND-AML, in the context of European LeukemiaNet (ELN) and Mayo Genetic risk models. Methods: ND-AML patients receiving Ven-HMA at the Mayo Clinic were retrospectively studied. Patients were stratified by ELN 2024 (Döhner Blood 2024) and Mayo Genetic risk (Gangat Am J Hematol 2025) , and analyzed using standard statistical methods. Results: 540 patients (median age 75 years, 52% de novo) received HMA with Ven for 7d ( n =33), 14d ( n =117), 21d ( n =96), or 28d ( n =294). ELN and Mayo risk distributions were 22%/35% high, 18%/56% intermediate, 60%/9% low risk, respectively. Baseline characteristics were comparable. CR/CRi rates were comparable across Ven durations, with the exception of lower CR/CRi with 7d vs 21d (p=0.04). Risk-stratified CR/CRi showed variations across Mayo and ELN groups but without significant differences based on Ven duration (Table). Allogeneic transplant rates were 15%, 18%, 18%, 20% for 7, 14, 21, 28d (p=0.86). At a median followup of 37.7 months, median overall survival (OS) differed by ELN risk (6.6, 11.9, 20 months) and Mayo genetic risk (7.8, 17.4 months, not reached (NR)), for high, intermediate, low risk (p<0.01), respectively. Median OS was comparable across Ven 7, 14, 21, 28 d (13, 13, 17, 14 months; p=0.84), with corresponding 1/3/5-year survival rates (Table). 30/60d mortality differed by Ven duration; 7d 10%/20%, 14d 7%/15%, 21d 4%/13%, 28d 4%/6%. Compared with 28d, 30d mortality was higher with 7d and 14d (p=0.07/0.03), and 60d mortality was higher with 7d, 14d, and 21d (p=0.02/0.01/0.05). OS was comparable across Ven durations within ELN intermediate/low risk and all Mayo risk groups, except among ELN high risk, patients receiving 14d Ven had inferior OS compared with 21d and 28d (p<0.01). Cumulative incidence of relapse at 1 year was similar among patients receiving 14, 21, 28d Ven (16%, 18%, 18%;p >0.1). Conclusions: Survival outcomes were comparable across Ven 7, 14, 21, 28 d in ND-AML, with outcomes driven by Mayo Genetic and ELN risk. Despite differences by Ven duration in high-risk groups, higher early mortality with 7d and 14d likely reflects treatment selection. Prospective trials are needed to establish risk adapted Ven dosing strategies. 7 (N=33) 14 (N=117) 21 (N=96) 28 (N=294) P-value CR/CRi (%) 52 63 72 65 0.19 7≠21 Mayo Risk High 33 49 58 55 0.53 - Intermediate 55 69 80 69 0.17 7≠21 Low 100 85 80 84 0.84 - ELN Risk High 33 30 57 53 0.21 - Intermediate 33 59 64 56 0.63 - Low 62 74 80 73 0.46 - Median OS (months) 13 13 17 14 0.84 - 1/3/5-year survival (%) 53/NR/NR 51/25/22 56/23/20 55/27/20 >0.1 -

OBJECTIVE Historically, craniopharyngioma (CP) was divided into adamantinomatous CP (ACP) and papillary CP (PCP) subtypes based on histopathological features. However, each harbors a unique genetic profile and progressively differing treatment paradigms, leading to their reclassification by the WHO in 2016 as two distinct entities. Descriptive in nature, this large multi-institutional study aimed to establish current differences between the presentation, treatment patterns, and clinical course of these pathologies to serve as a baseline for future studies as new treatment paradigms emerge. METHODS The authors queried the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, which encompassed patients from 14 participating institutions across the United States between 2000 and 2024. The database was screened for adult patients who underwent initial CP treatment with a confirmed histopathological diagnosis of ACP or PCP. Patient demographic characteristics, clinical course, tumor treatment, and outcomes data were collected and compared by CP type. RESULTS The final analysis included 273 ACP and 99 PCP adult patients who underwent initial surgical treatment. ACP patients presented younger on average (mean 48.3 vs 52.8 years, p = 0.034). PCP patients were more likely to present with hypothyroidism (33.3% vs 20.5%, p = 0.010), hyperlipidemia (25.3% vs 15.8%, p = 0.036), fatigue (28.3% vs 17.6%, p = 0.024), temperature intolerance (9.1% vs 1.5%, p < 0.001), and cardiac arrhythmia (6.1% vs 1.1%, p = 0.006). The groups demonstrated similar postsurgical and neuroendocrinological outcomes. Postoperative median (IQR) progression-free survival did not significantly differ between groups (19.0 [7.0–37.0] for ACP vs 5.0 [3.5–7.5] months for PCP, p = 0.972). ACP patients were more likely to receive radiation after surgery (27.8% vs 15.2%, p = 0.012). CONCLUSIONS This large multicenter descriptive study aimed to characterize similarities and differences between the clinical courses of molecularly distinct ACP and PCP, which has not previously been described. The findings should serve as a baseline to inform future studies, particularly with the recent introduction of targeted therapy for PCP.

Abstract Rationale Patients with interstitial lung disease related to systemic autoimmune rheumatic diseases (SARD-ILD) may develop progressive pulmonary fibrosis (PPF), characterized by irreversible loss of lung function and high mortality risk. The risk of PPF by SARD subtype is not well characterized in large, representative real-world data sources. We characterized patients with SARD-ILD and compared the risk of PPF by SARD subtype in a multicenter cohort derived from the national Patient-Centered Clinical Research Network (PCORnet). Methods Harmonized electronic health record (EHR) data was collected from seven PCORnet centers. Included patients had at least two ICD-9/ICD-10 codes for ILD between 2015-2021, an ILD diagnosis that persisted following chest CT and/or lung biopsy, at least one year of potential follow-up, and sufficient lung function data to assess PPF. The presence of SARD, subtypes of which were classified by ICD codes, was also required. PPF was defined by ≥ 5% absolute decline in FVC, lung transplantation or death. The incidence of PPF was compared across SARD subtypes using Kaplan Meier estimates and Cox proportional hazards models adjusted for age, sex, enrolling center and baseline FVC. Results The cohort included 6,288 patients with SARD-ILD, of whom 68.4% were female, with a mean (SD) age of 61.2 (13.9) years. The most common underlying SARD was rheumatoid arthritis (RA, 42.8%), followed by systemic sclerosis (SSc, 22.3%), mixed connective tissue disease (MCTD, 21.5%), Sjögren’s syndrome (16.9%), systemic lupus erythematosus (SLE, 14.5%) and polymyositis/dermatomyositis (PM/DM, 12.0%). Mean FVC and DLCO at baseline were 78.7 (22.9) % and 51.9 (21.3) % of predicted, respectively. Patients with PM/DM had the lowest mean FVC (70.4 [SD 21.3]) % of predicted) and DLCO (45.1 [SD 18.5] % of predicted). During the follow-up period, antifibrotic, corticosteroid, and non-steroidal immunosuppressive drugs were used by 7.6%, 89.3% and 77.5% of the overall cohort, respectively. The cumulative incidence of PPF, transplant or death at one year ranged from 20.6% to 29.0%, depending on SARD-ILD subtype, with higher risk among those with RA, SSc or MCTD as compared with PM/DM (figure). Conclusions In a large, harmonized EHR dataset, the risk of PPF at one year among patients with SARD-ILD was high. Variability of PPF risk by SARD-ILD subtype was similar to that observed in traditional cohort studies, with lower risk among patients with myositis despite poorer lung function at baseline. These findings establish the feasibility of PCORnet as a tool to understand PPF among patients with SARD-ILD. This abstract is funded by: Genentech

Abstract Introduction Pulmonary artery masses have a broad differential. CT may offer initial characterization, but cardiac MRI and PET/CT provide more definitive information. Histopathologic evaluation is often required. We present a rare case of a pulmonary artery mass with an elevated IgG4 index, initially misclassified as more common benign and malignant entities. Case-Presentation: A 61-year-old never smoking female was referred to the pulmonary clinic for abnormal imaging. Her history was only for patent ductus arteriosus repair in infancy. She initially presented with pleuritic chest pain and was found to have near occlusive mass in the distal main pulmonary artery extending into the proximal left main pulmonary artery. This was presumed to be pulmonary embolism, and anticoagulation was started. At presentation, she reported mild dyspnea and improving chest pain, without constitutional symptoms. Cardiac MRI revealed restricted diffusion and enhancement consistent with pulmonary artery sarcoma. PET-CT revealed FDG avid pulmonary artery mass (SUV max 14.5) without other hypermetabolic lesions. She subsequently underwent resection of the main and proximal left PA mass resection with bovine pericardial reconstruction. Histopathology showed a dense lymphoplasmacytic infiltrate with prominent plasma cell infiltration, IgG4/IgG ratio of 40%, and &gt; 10 IgG4 positive plasma cells per high power field. No histiocytic proliferation or evidence of other atypia. Her serum IgG4 level, CRP, ANCA serology, and fungal serology were normal. Discussion Here we present the case of isolated pulmonary artery mass with elevated IgG4 index of greater than 40% without other organ manifestations of IgG4 related disease (IgG4-RD). Cases of IgG4-RD related infiltration with a pulmonary artery mass have been reported, yet these typically present with other systemic manifestations, vascular inflammation, luminal stenosis, and/or pulmonary hypertension. Based on ACR 2019 IgG4 related disease classification criteria, these patients would not strictly meet criteria for IgG4 related disease. After extensive multidisciplinary discussion, we have elected to hold systemic treatment for IgG4-RD. She will be followed closely, monitoring new evidence of organ infiltration that would warrant systemic treatment. Conclusion Pulmonary artery masses should raise suspicion for various benign etiologies, such as chronic thromboembolism, and malignant entities, including pulmonary artery sarcoma. Cardiac MRI, PET/CT, and histopathology were critical in this patient’s evaluation. IgG4-related disease can rarely present as an intimal pulmonary artery mass. However, this is typically accompanied by systemic findings suggestive of IgG4-RD, other vascular infiltration, and/or pulmonary hypertension, all of which were absent in this patient. This abstract is funded by: None

Abstract Background For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes ( BRCA1, BRCA2, PALB2, ATM, CHEK2 ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion This flexible, variant-level methodology combines nationally-collected ‘enriched’ datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.