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e12749 Background: Breast cancer (BC) survivors are at higher risk for recurrence or new primary disease and often require complex surveillance imaging. Use of contrast enhanced surveillance imaging modalities with contrast-enhanced digital mammography (CEM) and magnetic resonance imaging (MRI) has increased in recent years. This study evaluates characteristics of those BC survivors who receive contrast enhanced imaging and whether the addition of contrast enhanced imaging affects biopsy outcomes in BC survivors. Methods: An IRB-approved retrospective chart review identified female BC survivors who underwent breast surgery and subsequent surveillance imaging at a single academic center between 2016 and 2025. Surveillance episodes were categorized as mammography alone versus mammography with addition of CEM and/or MRI. Multivariable generalized estimating equations were used to compare patient and tumor characteristics associated with enhanced imaging modality use. Similarly rates of biopsy and cancer were evaluated with enhanced imaging use. Results: A total of 4,050 surveillance imaging episodes in 861 patients were identified and 54 resulted in biopsy-proven malignancy. Mammography alone was performed in 3,459 episodes, while enhanced imaging with CEM or MRI was used in 591 (14.6%) episodes. Use of CEM or MRI for surveillance imaging increased over time. In 2016, surveillance imaging consisted predominantly of mammography alone (93.3%) with 6.6% incorporating MRI or CEM. By 2025, mammography only surveillance decreased to 78.4% while use of MRI or CEM increased to 21.6%. Use of contrast enhanced imaging was associated with higher incidence rate ratios (IRR) for dense breast tissue [IRR 2.33; 95% CI 1.92, 2.82), p < 0.001] and less frequently used among patients aged 65–79 years [IRR 0.60, 95% CI 0.49, 0.74; p < 0.0001] and > = 80 years of age [IRR 0.40; 95% CI 0.24, 0.66; p < 0.001]. Ductal carcinoma in situ (DCIS) (IRR 3.09, p = 0.0061), and immunotherapy use (IRR 2.56, p = 0.0006) also were associated with increased use of CEM/MRI enhanced imaging. Biopsies were performed in 146 (4.2%) mammography alone episodes and 55 (9.3%) enhanced imaging episodes [IRR 2.20; 95% CI 1.63, 2.96; p < 0.001]. Surveillance with mammography yielded malignant biopsy results in 39 (1.1%) episodes, compared with 15 (2.5%) episodes using enhanced imaging [IRR 2.25; 95% CI 1.25, 4.06; p = 0.007). Conclusions: In breast cancer surveillance at our institution, the addition of contrast enhanced imaging modalities were utilized in a minority of surveillance episodes but did increase over time and were higher in patients with dense breasts. CEM or MRI usage demonstrated higher biopsy rates and increased malignancy detection compared with mammography alone, but the incidence of a positive biopsy was low. These findings suggest and are in keeping with 2023 ACR guidelines that enhanced imaging may improve cancer detection in select breast cancer survivors.

9568 Background: Stage IIB/C cutaneous melanoma is associated with high recurrence risk, however stratification of risk in relation to time after surgery has not been comprehensively evaluated. We evaluated recurrence-free survival (RFS) at key time points, stratified by clinicopathologic factors, to identify patients (pts) at higher recurrence risk and personalize postoperative surveillance strategies. Methods: In this multi-institutional, international retrospective cohort study from the Sentinel Lymph Node Working Group database, we included pts with pathologic T3b/T4a/T4b and N0 disease who underwent surgical resection and sentinel node biopsy from 1994-2025. The type of first recurrence (local, regional, distant) was characterized based on time category (0-12, 12-24, 24-60, and 60+ months after surgery). Restricted mean survival time (RMST) analysis was used to measure the average survival time up to a specified time point (6-, 12-, 24-, and 60-months after surgery), and associations of clinicopathologic variables (age, sex, Breslow thickness, ulceration and lymphovascular invasion [LVI]) with RFS. Results: We included 2514 stage IIB/C pts from 19 sites in 4 countries, with a median follow-up of 53 (stage IIB) and 49 (stage IIC) months. 675 (27%) pts experienced a recurrence (92 [14%] local, 238 [35%] regional and 345 [51%] distant), and 400 (59%) recurrences occurred within 24 months. The proportion of distant recurrences as the first recurrence increased significantly with time, comprising 39%, 50%, 62%, and 59% of recurrences in the 0-12, 12-24, 24-60, and 60+ month time categories respectively (χ 2 p<0.001). No significant differences were observed for the included clinicopathologic variables for 6-month RMST estimates. At 12 months, RMST estimates for thickness ≥4 mm (11.2 vs 11.6 months for thickness 2-3.99 mm, p<0.001) and presence of LVI (10.7 vs 11.4 months, p=0.009) were significantly different. 24-month RMST estimates differed for male sex (20.7 vs 21.5 months vs females, p=0.002), thickness ≥4 mm (20.5 vs 21.9 months, p<0.001), and presence of LVI (19.0 vs 21.1 months, p<0.001). Lastly, 60-month RMST estimates differed for male sex (42.0 vs 45.2 months, p=0.001), thickness ≥4 mm (41.5 vs 46.2 months, p<0.001), LVI (36.0 vs 43.7 months, p<0.001), and age >65 years (41.5 vs 46.4 for age <42, p=0.022). Conclusions: In this real-world, multi-center analysis of pathologic stage IIB/C melanoma pts, recurrence patterns varied based on time after surgery. Breslow thickness, LVI, male sex, and age were significantly associated with earlier recurrence at different time intervals on RMST analysis. Additionally, given that >50% of first recurrences 12+ months after surgery were distant, active surveillance for distant relapses may be warranted.

With most states lacking comprehensive legislation addressing overdose preparedness in schools, there is an urgent necessity for prompt and effective solutions that accommodate existing resource constraints. Arizona, the primary entry point for over 55% of US fentanyl trafficking, responded to this critical public health challenge by initiating the nation’s first unfunded grassroots collaboration between community and government sectors to enhance statewide school overdose prevention and preparedness. The School Training, Overdose Preparedness and Intelligence Task force (STOP-IT) included more than 60 volunteers from the health care, legal, education, local government and behavioral health fields and worked collaboratively with the Arizona Department of Education to develop a response. Within 6 months of inception, STOP-IT conducted a comprehensive school survey to identify barriers to naloxone accessibility, created evidence-based school policies, established a sustainable and complimentary naloxone supply chain for schools with an ordering platform, and implemented a statewide naloxone distribution plan. The amassed resources were organized into a Fentanyl and Overdose Response Toolkit, widely disseminated to more than 2000 public, private, and charter schools. Moreover, STOP-IT launched both a local and national public information campaign to effectively raise awareness about the opioid crisis in schools. Using various media channels such as webinars, podcasts, media broadcasts, newsletters, and peer-reviewed publications, the campaign successfully amplified its message and enhanced community engagement. The STOP-IT initiative emerged as an innovative collaboration between government and community leaders, united in their mission to combat the growing opioid crisis in schools.

93 Background: Colorectal cancer (CRC) is the 4th most common cancer among men and women and roughly 2-4% of all CRCs occur in patients with a diagnosis of Lynch syndrome (LS), an autosomal dominant condition found to be the most common cause of hereditary CRC with estimated lifetime risk of developing CRC between 50-80%. LS results from mutations in one or more of 5 genes: MLH1, MSH2, MSH6, PMS2, and EPCAM, which lead to a deficiency in DNA mismatch repair ( dMMR ). Current guidelines suggest testing every CRC for microsatellite instability ( MSI ) or MMR gene expression using immunohistochemistry (IHC) to identify LS-related CRC. QuantCRC is a prognostic AI model that identifies important histological features of CRC and provides a recurrence prediction estimate useful for treatment decisions. It uses computational image analysis to extract quantitative features from digitized H&E stained pathology slides such as tumor grade, tumor-infiltrating lymphocytes, and other morphometric parameters. 4 It has been verified and validated in Aiforia (AI for image analysis) Platform using whole slide images and against reviews by independent pathologists from 8 hospitals. Our study sought to use QuantCRC to identify histological differences between those with MSI (confirmed LS), sporadic MSI , and microsatellite stability (MSS ) CRC to better help clinicians identify which patients would benefit from additional testing. Methods: We conducted a retrospective cohort study of patients with CRC whose pathology was analyzed at Mayo Clinic Arizona. Tumor characteristics were analyzed by QuantCRC and Receiver Operating Characteristic (ROC) curve analysis using Area Under the Curve (AUC) was used to see if QuantCRC could distinguish CRCs with MSI or LS. Results: Of the total 5132 patients with CRC, 1101 (21.5%) samples were MSI/dMMR with 468 (42.5%) of those having confirmed LS. The study had roughly equal parts men and there were more women with non-LS MSI (59%) than with LS or microsatellite stability. The QuantCRC model’s ROC analysis revealed an AUC of 0.83 for predicting MSI/dMMR among all patients with a sensitivity of 0.75 and a specificity of 0.79. AUC for predicting LS among all patients was 0.76 and of predicting LS among MSI/dMMR was 0.64. Conclusions: The QuantCRC model was useful in predicting MSI/dMMR status among all patients with CRC. It can be a helpful clinical tool when assessing which patients may benefit from additional genetic or IHC testing, especially in lower resource areas where molecular testing may be difficult to access or expensive relative to an H&E slide.

599 Background: Biliary tract cancers (BTC) remain aggressive malignancies with limited treatment options. Alterations in PIK3CA are implicated in tumor progression across solid tumors, but their prognostic impact in BTC remains unclear. We investigated the association of PIK3CA alterations(alt), alone and in combination with TP53 and ARID1A , with survival outcomes in advanced BTC. Methods: We conducted a retrospective analysis of 1,079 patients with advanced BTC treated with first-line chemotherapy (CT) or chemoimmunotherapy (CIO) across three sites in the USA, Japan, and Brazil. Genomic profiling was performed using next-generation sequencing on tissue and/or liquid biopsy samples. Survival outcomes were estimated by Kaplan-Meier analysis, with comparisons by log-rank testing and hazard ratios (HR) derived from Cox regression models. Results: PIK3CA alterations were identified in 11% (123/1,079) of patients. The median age at diagnosis was 68 yrs (range, 20–79), with 50% (62/123) female. The most common primary site was intrahepatic in 43.1% (53/123) while majority of patients received CT only 92.5% (111/123). When analyzed with TP53 , 68 pts had PIK3CA/TP53 co-alterations(co-alt), 501 had TP53 alt, 55 had PIK3CA alt alone, and 455 had neither PIK3CA nor TP53 alt (WT/WT). Overall survival (OS) was significantly worse in patients with PIK3CA alt, particularly in the setting of TP53 co-alt. Median OS (mOS) was 22.6 months(m) (95% CI, 20.4–24.8) for PIK3CA/TP53 WT, 15.9 m (95% CI, 11.6–18.5) for PIK3CA alt /TP53 WT, 14.6 m (95% CI, 13.1–19.5) for PIK3CA alt/ TP53 alt, and 17.1 m (95% CI, 15.5–18.8) for TP53alt/PIK3CA WT (p<0.001). In analyses with ARID1A , 32 pts had PIK3CA/ARID1A co-alt, 91 had ARID1A alt only, 120 had PIK3CA alt only, and 836 were WT/WT. PIK3CA/ARID1A co-alt tumors had a mOS of 12.8 m (95% CI, 9.1–NE) compared with 19.3 m (95% CI, 18.1–20.9) in PIK3CA WT /ARID1A WT (p=0.009). Multivariate analysis identified PIK3CA alt (hazard ratio [HR] 1.37, 95%CI 1.09–1.72; p=0.008), PIK3CA alt/ TP53 alt (HR 1.52 95% CI, 1.11–2.07; p=0.008), ARID1A alt/ PIK3CA WT (HR 1.40, 95% CI 1.08-1.82, p=0.011), and metastatic status (HR 1.82, 95% CI 1.52-2.19, P<0.001) as independent prognostic factors for shorter OS. Conclusions: In advanced BTC, PIK3CA alt were associated with significantly worse overall survival, particularly when co-occurring with TP53 or ARID1A alt. These findings establish PIK3CA as a prognostic biomarker of poor outcome and highlight the need to explore PI3K-targeted therapeutic strategies in BTC.

Abstract Background: The functional importance of bone marrow adipocytes (BMA) is frequently overlooked even though they are critical components of the BM (bone marrow) microenvironment. BMA have been proposed to play a supportive role within the hematopoietic niche and to directly sustain hematopoietic stem cell (HSC) survival as well as to preferentially support leukemia cell survival and proliferation (Sabbah Cell Commun Signal 2023). Although significant ex-vivo data implicates direct and indirect crosstalk between BMA and neoplastic HSCs (Venti Front Endocrinol 2022), the possible role of BMA in myeloproliferative neoplasms and their dynamics following therapy have yet to be characterized. Adiponectin, an anti- inflammatory adipokine that maintains metabolic homeostasis through regulation of insulin sensitivity, lipid metabolism and pro-inflammatory signaling is low in MPN patients and increases with IFN-α therapy (Avcu Int J Hematol. 2006). IFN-α has also been implicated in inhibiting adipogenesis via JAK-STAT1 signaling (Lee Biochim Biophys Act. 2016). A single institutional study of IFN-α in patients with essential thrombocythemia (ET) and polycythemia vera (PV) confirmed the potential for BM histopathologic responses and a correlation with molecular responses (Masarova Exp Hematol Oncol 2017). The aim of this analysis was to characterize the change in BM cellularity and fat composition with pegylated IFN α-2a (Pegasys; PEG) and the relationship with both hematologic and molecular response from tissue collected in prospective, global clinical trials of PEG in patients with ET/PV. Methods: A total of 24 subjects from the phase 2 MPN-RC 111 (Yacoub Blood 2019) salvage PEG study and 16 subjects from the MPN-RC 112 (Mascarenhas Blood 2022) phase 3 study comparing PEG to HU with available clinical, BM H&E slides, laboratory and molecular data were included in this retrospective analysis of prospective clinical trial data. We assigned a semi-quantitative score for changes in cellularity, fat distribution, and megakaryocyte (MK) histo-topography for changes from baseline, at 12, 24 and 36 months when available. Changes in BMA content and para-trabecular distribution were assessed on whole slide digital images with machine learning models. BMA content was quantified with a QuPath pixel classifier that distinguished adipocytes from other marrow components (Bankhead Scientific Reports 2017). Para-trabecular adipocyte distribution was assessed by leveraging UNI2-h, a self-supervised Vision Transformer (ViT-H/14) model and successor to UNI (Mahmood Nature 2024). UNI2-h was pre-trained on 200 million image tiles from over 300,000 H&E and IHC slides. In this study, UNI2-h was adapted to distinguish between high and low para-trabecular adiposity using image tiles centered on trabeculae. Trabeculae with a surrounding layer of adipocytes were labeled as ‘high’ adiposity, while ‘low’ para-trabecular fat distribution was defined by the direct contact of cellular marrow with trabeculae, lacking surrounding adipocytes. Results: A total of 40 PEG-treated ET (n=18) and PV (n=22) patients were included in this analysis with a median age of 64 years (26-85), 77% JAK2V617F+, 23% CALRmut+, and 40% treatment-naïve. The median JAK2V617F variant allele fraction (VAF) was 26% (range 3-96%). A complete hematologic response (CHR) was obtained with PEG in 58%, 61% attained &gt;20% reduction in driver VAF and 48% attained a &gt;50% reduction in VAF (MR) within 24 months of baseline. We observed an increase in BMA content and notable increase in para-trabecular distribution (confirmed by morphology and ML, independently) in 93% and 53% of PEG treated patients attaining a MR versus only 31% and 6% who did not attain MR, respectively (P Value=0.0004). There was more notable improvement towards normalization of MK histo-topography and orderly erythropoiesis in MR (86.6%) than in non-MR (31.2%) (P value=0.001). Increase in BMA content, BMA para-trabecular distribution, or improvement in MK histo-topography were not associated with achievement of CHR or changes in CALR VAF in this small cohort. Cytokine correlation with BMA dynamics is currently ongoing and will be reported at the meeting. Conclusion: Treatment of MPN patients with IFN-α resulted in reproducible changes in BM cellularity including MK histo-topography, erythropoiesis, BMA number and distribution. Changes in BMA were closely associated with reduction in JAK2V617F VAF following PEG treatment.

Abstract Introduction Persistent symptom burden in classic myeloproliferative neoplasms (MPNs) i.e., polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) is linked to shorter survival, more thromboembolic events and impaired quality of life. Identifying demographic, clinical, laboratory, and treatment-related predictors of symptom improvement can inform risk-adapted care and guide supportive interventions. Methods Patients with PV, ET, and MF were identified through a retrospective chart review. Total symptom scores (TSS) and scores of individual symptoms were recorded at the time of first TSS assessment. Demographic (age, sex, race, ethnicity), seasonal (summer: April–September; winter: October–March), clinical (time since diagnosis, depression, obesity, spleen size), treatment-related (phlebotomy, hydroxyurea, interferon-alpha, anagrelide, JAK inhibitors, antidepressants) and laboratory (complete blood counts, serum chemistry) factors were captured at the baseline. Symptom improvement was defined as a ≥50% TSS reduction from baseline. Cumulative incidence analyses, accounting for death as a competing risk, were performed to estimate the probability and timing of symptom improvement. Multicollinearity was assessed using variance inflation factors (VIFs). Highly correlated (VIF ≥5) features and features with ≥15% missing observations were excluded. Multivariable Fine-Gray hazards regression was performed to identify predictors of symptom improvement. Sub-distribution hazard ratios (sHR) with 95% confidence intervals (CI) were computed with p-values &lt;0.05, indicating a statistically significant association with symptom improvement. Results A total of 532 patients (PV: 195, ET: 180, MF: 157) were identified between 2019 and 2024. The median age was 65 (IQR: 57-74) for PV, 65 (52-75) for ET, and 69 (63-75) for MF. Most patients were White (PV: 178, ET: 164, MF: 145) and female (PV: 99, ET: 134, MF: 84). Fatigue was the most frequently reported symptom (PV: 161, ET: 155, MF: 136) whereas weight loss was the least reported (PV: 9, ET: 12, MF: 26). Baseline TSS was highest in MF (median: 15; IQR: 7-27) followed by PV (13; 6-25) and ET (13; 5-23). Symptom improvement was observed in 89 (46%) PV, 71 (39%) ET, and 44 (28%) MF patients. Among those who improved, the cumulative incidence of symptom improvement reached 100% by 55 months in PV, 53 months in ET, and 58 months in MF. At 6, 12, and 24 months, cumulative symptom improvement was 22%, 34%, and 57% in PV; 15%, 25%, and 43% in ET; and 19%, 28%, and 39% in MF. Median time to improvement was not reached in any group. Death before symptom improvement was observed in 5 (3%) PV, 6 (3%) ET, and 37 (24%) MF patients. Multivariable regression analyses in PV identified higher baseline TSS (sHR: 1.02; 95%CI: 1.01-1.03) as associated with symptom improvement (p = 0.02). In ET, lower white blood cell count (sHR: 0.89; 95%CI: 0.81-0.98) and less time since diagnosis (0.99; 0.98-0.99) were associated with symptom improvement (p = 0.02). In MF, more months since diagnosis (sHR: 1.01 95%CI: 1.01-1.01) was associated with symptom improvement (p = 0.01). Conclusions Symptom trajectories differed across MPN subtypes. In PV, a higher baseline symptom burden; in ET, a lower white blood cell count and more recent diagnosis and in MF, a longer disease duration were associated with symptom improvement. These readily available parameters may help inform supportive strategies, tailor response expectations, and identify patients for symptom-directed interventions or clinical trials.

Abstract Background/rationale Primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia (Post-PV/ET MF) (collectively termed MF) are chronic hematopoietic malignancies with progressive bone marrow collagen fibrosis, peripheral cytopenias, extramedullary hematopoiesis, splenomegaly, debilitating constitutional symptoms and heightened risk of transformation to acute leukemia. The only currently approved therapies for MF are JAK inhibitors (JAKi) which can provide significant improvements in splenomegaly and systemic symptoms but do not fundamentally change the pathogenesis of the disease. As a result, additional non-JAKi therapies for patients with MF after JAKi failure represent an important translational focus. Reparixin is a novel, potent and specific inhibitor of the chemokine CXCL8 (IL)-8. IL-8 is a member of a class of cytokines involved in leukocyte recruitment and activation in tissues. There are two known types of CXCL8 receptors – CXCR1 and CXCR2, which are expressed in neutrophils (Baggiolini M, Adv Immunol 1994). IL-8/CXCR1/2 signaling has been shown to be a key mediator of inflammatory signaling in MF patients. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an exogenous CXCL8 ligand in vitro. Genetic deletion or a small molecule inhibitor of CXCR2 in MF mouse adoptive transfer models ameliorates fibrosis, extends overall survival and improves hematologic parameters (Dunbar A, Blood 2023). This pre-clinical data validates targeting this pathway in clinical investigations. Study design This is an open-label, phase II study assessing the efficacy, safety, and tolerability of reparixin in patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-2, or high-risk PMF, post ET/PV MF either after prior treatment with, or those who are ineligible for treatment with a JAKi. Patients will receive oral reparixin 1200 mg three times daily on a four-week cycle for a core study period of 24 weeks. Patients who achieve at least clinical improvement (CI) or stable disease (SD) with one grade improvement in bone marrow fibrosis by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria at the Cycle 7 response assessment may continue receiving reparixin until loss of response, disease progression, unacceptable toxicity, patients/physician withdrawal, or termination of study by sponsor. The study monitors both efficacy and toxicity using a Bayesian Optimal Phase 2 (BOP2) design. If response is observed in at least one patient out of 10 and safety is confirmed at the interim analysis, the trial will proceed to full enrollment of 26 patients. If more than three responses are observed in the total cohort, then a signal of activity is confirmed. Primary Objective: To estimate the efficacy of reparixin treatment in DIPSS intermediate-2 or high-risk subjects with PMF, post PV-MF, or post ET-MF. Secondary Objectives: To assess the efficacy of reparixin as determined by response assessment using IWG-MRT/ELN criteria at the end of Cycle 6 and Cycle 12. To assess the change in bone marrow fibrosis grade at the end of Cycle 6 and Cycle 12 with reparixin. To assess the safety of reparixin as measured by the adverse event profile of Common Terminology Criteria for Adverse Events v5.0. To assess spleen volume reduction by imaging after Cycle 6 and Cycle 12 as compared to baseline spleen volume. Key Exploratory Objectives: To evaluate changes in quality of life and patient-reported outcomes To conduct correlative studies to measure biomarkers of reparixin activity, such as Vascular Endothelial Growth Factor (VEGF) levels, bone marrow microvessel density, megakaryocyte number and peripheral blood CD34+ cell number, and patients with and without IL-8 secretion. Key inclusion criteria: Have a pathologically confirmed diagnosis of PMF, post-ET-MF, or post-PV-MF as per the WHO diagnostic criteria with intermediate-2 or higher risk disease by DIPSS Be refractory/resistant to or intolerant of/inappropriate for JAKi therapy Have adequate liver and kidney function Platelet count ≥ 25 x 109/L Bone marrow and peripheral blood blast count &lt; 10% ANC ≥ 1000 mm3. MPN Research Consortium (MPN-RC) 120 is currently enrolling patients through the MPN-RC clinical sites throughout the United States. Clinical Trial Identifier NCT05835466

Abstract Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) for which the only approved therapies are JAK inhibitors which improve splenomegaly and disease-related symptoms. Inflammatory pathways beyond JAK-STAT are critical in the pathobiology of MF and contribute to patients' clinical manifestations. IL-1β is a master regulator of inflammation which is overexpressed in MPNs, preferentially supports the MPN mutant stem cell, and interacts with key cytokines that are implicated in fibrogenesis, inflammatory symptoms, and disease progression. Knockout of IL-1β in MPN mouse models led to an abrogated clinical phenotype, while pharmacologic inhibition of IL-1β resulted in reduction of reticulin fibrosis and osteosclerosis. Canakinumab is a fully human monoclonal antibody that binds to and neutralizes IL-1β. It is approved for rare inflammatory disorders with a safety profile that has been extensively studied in the CANTOS trial that assessed cardiovascular outcomes in high-risk patients (pts). Based upon these data, we designed a phase 2 study of canakinumab in pts with MF. Methods NCT05467800 is a Myeloproliferative Neoplasm Research Consortium (MPN-RC) ongoing open-label, 2-part, phase 2 study of canakinumab in pts with MF. Part 1 enrolled pts with MF previously treated with or ineligible to receive a JAK inhibitor. Canakinumab was given subcutaneously at a dose of 200mg on day 1 of 21-day cycles. Primary response assessment occurred at week 24 following cycle 8. Responding pts could continue to receive canakinumab. Eligible pts had platelets &gt;25 x109/L and a need for MF-directed therapy defined as ≥ 1 of the following: hemoglobin &lt;10 g/dL, transfusion dependency, splenomegaly palpated ≥ 5cm below left costal margin, and/or MPN-SAF version 4.0 TSS ≥ 10. The primary endpoint was overall response rate (ORR) including CR, PR, or CI after 8 cycles (24 weeks). A Bayesian optimal phase 2 (BOP2) design was used with an interim analysis performed after 10 pts. Results In part 1, 14 pts were enrolled and 13 were treated. One pt discontinued prior to starting treatment due to rapidly progressive disease. Enrollment onto part 1 has closed with 2 pts remaining on treatment. Median age was 70 y (range: 55-83). Eleven (84.6%) pts had received prior ruxolitinib. Median hemoglobin was 8.2 g/dL (range: 5.7-13.2), median platelet count was 114 x 109/L (range: 21-484), and median WBC was 9.7 x 109/L (range: 2.4-71.4). Five (38.5%) pts were transfusion dependent. Median MF-SAF TSS at baseline was 15 (range: 4-46). Median spleen volume at baseline was 1522 cm3 (range: 362cm3-2997cm3). Pts received a median of 9 cycles (range: 2-19). Three (23%) pts responded at week 24, achieving a CI-symptom response (TSS50). Six (46%) pts experienced progression of disease due to spleen volume increase. Median hemoglobin was 8.2 g/dL at baseline, 7.9 g/dL at week 12, and 9.0 g/dL at week 24. Median platelet count was 114 x 109/L at baseline, 98 x 109/L at week 12, and 183 x 109/L at week 24. Median MF-SAF TSS declined from 15 at baseline to 10 at week 12 and 9 at week 24. Eleven (85%) pts exhibited symptom improvement during treatment (MF-SAF TSS percent change from baseline range -20% to -85%). In pts with baseline hsCRP ≥ 1.0 (n = 8), canakinumab led to a reduction at week 24 (or EOT if prior to week 24) in 5/8 (62.5%) with a median decrease in CRP of 37%. The most common adverse events (AEs) were anemia and thrombocytopenia and often attributed to underlying disease. Non-hematologic grade ≥ 3 AEs occurred in 3 pts and were deemed unrelated to canakinumab, except for one grade 3 increase in bilirubin that was possibly related per the treating physician. Conclusion The IL-1β inhibitor, canakinumab, resulted in consistent symptom improvement and exhibited beneficial impact on cytopenias in pts with R/R MF while demonstrating a manageable toxicity profile. Consistent with pre-clinical data, inhibition of IL-1β had little impact on splenomegaly, an observation that was likely enhanced by frequent JAK inhibitor discontinuation prior to study start. Given the encouraging impact on MF symptoms, blood counts and reassuring safety profile, the study was amended to enroll pts on a stable dose of a JAK inhibitor (ruxolitinib, fedratinib, momelotinib, or pacritinib) who have the potential to benefit from additional therapy. Part 2 is currently enrolling at multiple sites and updated clinical and correlative data will be presented at the meeting.

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