Thukral, Jatin

e18609 Background: Anemia is a frequent complication of myelofibrosis (MF) and is embedded in widely used prognostic systems, yet contemporary real-world estimates of its association with long-term survival and leukemic transformation remain limited. We evaluated the impact of baseline anemia (hemoglobin [Hb] <10 g/dL) on overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in adults with MF. Methods: We performed a retrospective cohort study using the TriNetX Research Network, identifying adults (≥18 years) with myelofibrosis and stratifying them by anemia status at index (Hb <10 g/dL). Patients with the outcome of interest prior to each analytic window were excluded. To minimize confounding, cohorts were 1:1 propensity score–matched using nearest-neighbor matching with a caliper of 0.1 pooled standard deviations of the logit of the propensity score, adjusting for demographic factors, comorbidities, iron supplementation, leukocyte count, and platelet count. Balance was assessed using standardized mean differences <0.1. The primary outcome was all-cause mortality and the secondary outcome was transformation to AML, assessed at 1, 3, and 5 years. Risk estimates were calculated, and survival analyses were performed using Kaplan–Meier curves and Cox proportional hazards models, with statistical significance defined as a two-sided p<0.05. Results: After matching, 18,504 patients with MF were identified, of which 51.6% were females and 48.3% were males. The mortality rate in patients with anemia was higher than in those without at years 1, 3, and 5: 21.4%, 33.2%, and 39%, respectively, versus 5.4%, 12%, and 16.9%, respectively. The prevalence of transformation to AML was also higher in patients with anemia at 3.7%, 4.9%, and 5.3% at years 1, 3, and 5, respectively, versus 0.1%, 0.3%, and 0.4% in patients without anemia at those same time points. The HR for mortality in MF patients with anemia when compared to those without anemia at years 1, 3, 5 was statistically significant at 4.57 (95% CI 4.14-5.05, log-rank p<0.01), 3.51 (95% CI 3.28-3.76, log-rank p<0.01), and 3.04 (95% CI 2.87-3.23, log-rank p<0.01) respectively. The HR for transformation to AML in patients with MF with anemia versus those without anemia was statistically significant at years 1, 3 and 5, with HRs of 34.96 (95% CI 19.17-63.75, log-rank p<0.01) 20.75 (95% CI 13.97-30.83, log-rank p<0.01) and 17.07 (95% CI 12.11-24.07, log-rank p<0.01), respectively. Conclusions: In this large, propensity-matched real-world EHR analysis, baseline Hb <10 g/dL was associated with substantially worse OS and a markedly higher risk of AML transformation through 5 years. These findings support anemia as a pragmatic risk marker to inform risk-adapted monitoring, supportive care, and therapeutic decision-making in MF.

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.

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.

e16304 Background: Hepatic reserve is a critical determinant of outcomes in hepatocellular carcinoma (HCC), yet traditional scoring systems such as MELD are frequently unavailable or underpowered in real-world datasets. The albumin–bilirubin index (ALBI) is a validated, objective measure of liver function derived from routine laboratory values and has emerged as a pragmatic alternative for risk stratification. However, the impact of ALBI on longitudinal outcomes following locoregional therapy (LRT) for HCC in routine clinical practice remains incompletely characterized. Methods: We performed a retrospective cohort study using TriNetX to identify adults with HCC treated with locoregional therapies (transarterial chemoembolization, yttrium-90 radioembolization, stereotactic body radiation therapy, or thermal ablation). Hepatic reserve was assessed using an albumin–bilirubin–based definition with labs within 30 days pre-therapy. Low ALBI (preserved function) was defined as albumin ≥3.5 g/dL and bilirubin ≤2.0 mg/dL, and high ALBI (impaired function) as albumin < 3.5 g/dL or bilirubin > 2.0 mg/dL. Propensity score matching (1:1) balanced demographics and comorbidities. Outcomes at 6 months, 1, 3, and 5 years included mortality, hepatic failure, ascites, portal hypertension, and esophageal varices. RD, RR, OR, and HR with 95% CIs were reported. Results: After matching, 509 patients were included in each ALBI group. High ALBI was consistently associated with significantly worse outcomes across all time points. Overall mortality was higher in the high-ALBI group at 6 months (19.6% vs 8.7%), 1 year (31.0% vs 13.9%), 3 years (51.0% vs 28.3%), and 5 years (57.1% vs 35.6%). Corresponding hazard ratios for mortality ranged from 2.32 to 2.65 across time points (all p < 0.05). High ALBI was also associated with substantially increased risks of hepatic failure (5-year RD 23.9%, HR 3.29), ascites (5-year RD 18.5%, HR 2.50), and esophageal varices (5-year RD 8.5%, HR 2.60). These associations persisted from early through long-term follow-up, demonstrating durable prognostic separation by ALBI status. Conclusions: In this large, real-world cohort of HCC patients undergoing locoregional therapy, impaired hepatic reserve as defined by a high albumin–bilirubin index was strongly and consistently associated with worse short- and long-term survival and higher rates of hepatic decompensation. An albumin–bilirubin–based ALBI classification represents a pragmatic and clinically meaningful tool for risk stratification when MELD is unavailable and may inform treatment selection, prognostication, and post-therapy surveillance in routine clinical practice.

8597 Background: Lorlatinib improves outcomes in NSCLC but commonly causes marked hyperlipidemia, prompting initiation of lipid-lowering therapy (LLT). Beyond lipid control, LLT may be associated with vascular events; however, its association with thromboembolism, healthcare utilization, and mortality among lorlatinib-treated patients has not been characterized in real-world cohorts. Methods: Using TriNetX, we identified adults with NSCLC who received lorlatinib (index = first lorlatinib record). Patients were grouped by early LLT initiation within 30 days of index versus no LLT within 30 days. LLT included statins, ezetimibe, PCSK9 inhibitors, or fibrates. Cohorts were balanced 1:1 using propensity score matching on demographics and baseline comorbidities. Outcomes were assessed through 365 days; patients with prior outcome documentation were excluded. Results: After matching, 387 patients per cohort were analyzed. Early LLT was associated with lower all-cause mortality at 365 days (16.1% vs 26.4%; risk ratio [RR] 0.61, 95% CI 0.46-0.81; p=0.0004) and improved time to death (hazard ratio 0.60, 95% CI 0.44-0.82). Early LLT was also associated with lower venous thromboembolism (6.2% vs 12.1%; RR 0.51, 95% CI 0.30-0.86; p=0.0093) and fewer inpatient hospitalizations (14.6% vs 23.6%; RR 0.62, 95% CI 0.40-0.97; p=0.0320). Emergency department visits were numerically lower (8.3% vs 13.9%; RR 0.59, 95% CI 0.35-1.00; p=0.0467). No significant differences were observed for acute kidney injury or major adverse cardiovascular events. Conclusions: In a real-world propensity-matched cohort of lorlatinib-treated NSCLC patients, LLT initiated within 30 days was associated with lower 1-year mortality, venous thromboembolism, and hospitalization. Given the frequency of lorlatinib-associated dyslipidemia, these findings support early lipid monitoring and timely LLT initiation in practice. Prospective studies are warranted to confirm these associations. 365-day outcomes after matching. Outcome Early LLT (n=387) No early LLT (n=387) RR (95% CI) HR (95% CI) p All-cause mortality 16.1% 26.4% 0.608 (0.458-0.806) 0.597 (0.435-0.818) 0.0004; log-rank 0.001 Venous thromboembolism 6.2% 12.1% 0.509 (0.302-0.857) — 0.0093 Inpatient hospitalization 14.6% 23.6% 0.619 (0.396-0.967) — 0.0320 ED visit 8.3% 13.9% 0.593 (0.352-1.001) — 0.0467 Acute kidney injury 5.4% 7.1% 0.769 (0.429-1.378) — 0.3758 MACE 4.6% 4.6% 1.006 (0.511-1.979) — 0.9868

7041 Background: CD20×CD3 bispecific antibodies and CD19-directed CAR T-cell therapies are increasingly used in relapsed/refractory DLBCL. CAR T therapy is associated with higher rates of CRS,ICANS, and cytopenias, whereas bispecific antibodies are often perceived as less toxic and more outpatient-friendly. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adult patients with DLBCL treated with bispecific antibodies (glofitamab, epcoritamab) were compared with those receiving commercial CAR T-cell therapy (tisa, liso, axi). Propensity score matching was performed on demographics, comorbidities, baseline laboratory values, and corticosteroid exposure, yielding 468 patients per cohort. Outcomes included CRS, ICANS, severe neutropenia (ANC <500/µL), and thrombocytopenia (platelets <50×10³/µL), as well as hospitalization and ICU admission at 1, 3, 6, and 12 months. Overall survival (OS) was assessed using Kaplan–Meier analysis with log-rank testing. Results: After matching, CAR T therapy was associated with significantly higher immune-mediated toxicity. CRS occurred more frequently with CAR T at 1 month (37.4% vs 22.4%), 3 months (39.3% vs 27.6%), 6 months (40.6% vs 28.8%), and 12 months (41.2% vs 29.7%) (all p<0.001). ICANS was also more common with CAR T across all timepoints (1 month: 10.5% vs 4.9%; 12 months: 12.6% vs 7.5%). Severe neutropenia and thrombocytopenia were markedly more frequent in the CAR T cohort, with neutropenia affecting 66.7% vs 12.8% at 1 month and 71.6% vs 32.7% at 12 months (all p<0.001). Despite higher toxicity, healthcare utilization was comparable. Hospitalization rates were similar between groups at 1 and 3 months (61.8% vs 66.7% and 67.1% vs 75.9%), and ICU admission rates did not differ meaningfully at any timepoint. Importantly, overall survival consistently favored CAR T therapy. Survival differences emerged early and persisted over time, with lower mortality in the CAR T cohort at 1 month (2.1% vs 9.0%), 3 months (7.7% vs 18.6%), 6 months (15.8% vs 26.7%), and 12 months (26.5% vs 35.3%), corresponding to significantly improved OS by log-rank testing at all timepoints (p<0.001). Conclusions: In this large, real-world, propensity-matched analysis of relapsed/refractory DLBCL, CAR T-cell therapy was associated with substantially higher rates of CRS, ICANS, and severe cytopenias compared with bispecific antibodies. However, these toxicities did not translate into higher hospitalization or ICU utilization. Despite a less favorable early toxicity profile, CAR T therapy conferred a consistent and clinically meaningful survival advantage from early to late follow-up. Early toxicity alone should not preclude CAR T referral in appropriate candidates, underscoring the need for optimized patient selection, sequencing strategies, and supportive care.

5079 Background: Treatment sequencing in metastatic castration-resistant prostate cancer (mCRPC) after ADT and ARPI exposure varies in practice. While 177 Lu-PSMA use is expanding in routine practice, real world head to head comparisons with docetaxel in ARPI-exposed mCRPC are limited, particularly for short-term outcomes and treatment related acute care utilization. Methods: Using TriNetX, adults > 18 years of age with metastatic prostate cancer and prior ARPI exposure who initiated 177 Lu-PSMA or docetaxel were identified (index = first administration). Cohorts were balanced with 1:1 propensity score matching (PSM) on demographics and baseline comorbidities. Outcomes from day 1–180 post-index included all-cause mortality (primary), hospitalization, acute kidney injury (AKI; ICD-10 N17), and thromboembolic/ischemic events (ICD-10 I21/I26/I63/I82). For each outcome, patients with prior documentation of that outcome were excluded. Outcomes are reported as risks and risk ratios (RR) with 95% confidence intervals. Results: Before matching, 563 patients initiated 177 Lu-PSMA-617 and 8,749 initiated docetaxel; after 1:1 PSM, 497 patients per cohort were analyzed. At 180 days, all-cause mortality was 7.3% (36/494) with 177 Lu-PSMA-617 versus 12.2% (60/491) with docetaxel (RR 0.60, 95% CI 0.40–0.88). Hospitalization occurred in 7.2% (21/290) versus 21.1% (52/247) (RR 0.34, 95% CI 0.21–0.55). In a separate matched renal-safety analysis (480 per cohort), AKI occurred in 2.8% (11/390) versus 9.0% (36/399) (RR 0.31, 95% CI 0.16–0.60). Thromboembolic/ischemic events were 3.8% (15/394) versus 6.4% (26/404) (RR 0.59, 95% CI 0.32–1.10). Conclusions: In ARPI-exposed mCRPC, 177 Lu-PSMA was associated with lower 180-day mortality risk and substantially fewer hospitalizations than docetaxel, with a lower risk of AKI. These findings highlight a potential short-term effectiveness and acute-care utilization advantage of 177 Lu-PSMA in routine practice and support further prospective evaluation. Key 180-day outcomes after matching. Outcome 177 Lu-PSMA Docetaxel Effect estimate (180 days) All-cause mortality 36/494 (7.3%) 60/491 (12.2%) RR 0.596 (0.402-0.884) Hospitalization 21/290 (7.2%) 52/247 (21.1%) RR 0.344 (0.213-0.554); Acute kidney injury (AKI)* 11/390 (2.8%) 36/399 (9.0%) RR 0.312 (0.163-0.595) Thromboembolic/ischemic† 15/394 (3.8%) 26/404 (6.4%) RR 0.592 (0.318-1.100) *AKI analysis used a separate matched run (480 per cohort). †Composite of I21, I26, I63, I82.

Chimeric antigen receptor (CAR)-based therapies have become an integral part of modern cancer care, delivering durable responses in patients with otherwise refractory hematologic malignancies. As their use has expanded, it has become increasingly clear that these immune-based treatments exert important effects on the cardiovascular system. Rather than reflecting isolated cardiac injury, CAR-associated cardiovascular complications arise from a broader inflammatory process in which immune activation, cytokine release, endothelial dysfunction, and myocardial stress are closely interconnected. Pro-inflammatory mediators such as interleukin-6, interleukin-1β, tumor necrosis factor-α, and interferon-γ play central roles in shaping these responses, particularly during cytokine release syndrome. From a clinical perspective, cardiovascular manifestations often include hypotension, arrhythmias, and transient reductions in left ventricular function, with more severe presentations occurring in patients who develop high-grade inflammatory toxicity. At the same time, advances in immune engineering are reshaping how these platforms are viewed, extending their relevance beyond toxicity alone. Preclinical studies now suggest that CAR-based approaches may be adapted to modulate cardiac fibrosis and promote myocardial repair, highlighting a potential shift from purely oncologic applications toward broader cardiovascular benefit. Placing these developments within a cardio-oncology framework emphasizes the need for careful cardiovascular assessment, longitudinal monitoring, and close collaboration between specialties.

The therapeutic landscape of hematologic malignancies has undergone a paradigm shift with the increasing incorporation of targeted therapies, including inhibitors of vascular endothelial growth factor (VEGF) signaling. While VEGF-directed agents have historically been developed and deployed in solid tumors, their application in hematologic cancers—particularly multiple myeloma, select leukemias, and rare lymphomas—has expanded in investigational and clinical settings. VEGF is fundamental to angiogenesis, maintenance of endothelial integrity, and regulation of vascular tone. As a result, therapeutic inhibition of VEGF signaling is associated with a characteristic spectrum of cardiovascular adverse effects. These include hypertension, endothelial dysfunction, heart failure, thromboembolic complications, and renal injury, all of which present important clinical challenges in patients with hematologic malignancies. This population frequently has additional vulnerability due to factors such as cytopenias, preexisting renal impairment, and prior exposure to cardiotoxic anticancer therapies. This review aims to provide a cardio-oncology–oriented overview of VEGF biology, the range of VEGF-targeted agents used in hematologic cancers, and the underlying mechanisms driving their cardiovascular toxicities.

Advances in cancer therapeutics have substantially improved survival across multiple malignancies but have concurrently increased the burden of cancer therapy–related cardiovascular toxicity, establishing cardio-oncology as an essential discipline situated at the interface of oncology and cardiovascular medicine. Despite growing incorporation of cardiac imaging and circulating cardiac biomarkers into surveillance strategies, current approaches remain limited by modest specificity, heterogeneous risk profiles, and inconsistent translation into effective cardioprotective interventions. This review synthesizes contemporary evidence on the biological mechanisms underlying cancer therapy–related cardiovascular toxicity and critically evaluates the current role and limitations of established cardiac biomarkers, including high-sensitivity cardiac troponins and natriuretic peptides, in risk stratification and early injury detection. We further examine why many cardioprotective clinical trials have yielded neutral or modest results, highlighting signal dilution arising from low-risk populations, endpoint heterogeneity, and timing mismatches between injury biology and intervention. This review advances a precision cardio-oncology framework by integrating tumor-derived liquid biopsy platforms—such as circulating tumor DNA, tissue-specific cell-free DNA, and extracellular vesicles—with cardiac biomarkers to provide a biologically contextualized assessment of cardiovascular risk. Tumor-derived biomarkers may reflect treatment intensity, systemic inflammatory burden, and cardiotoxic susceptibility, thereby enhancing the interpretation of cardiac biomarker signals and refining patient selection for targeted cardioprotective strategies.