Gillani, Syed A

Abstract Background: Luspatercept, an erythroid maturation agent, has shown efficacy in improving anemia in both β-thalassemia and lower-risk myelodysplastic syndromes (MDS). In the BELIEVE trial, which led to its approval in transfusion-dependent β-thalassemia, thromboembolic events were notably higher in patients with risk factors such as splenectomy. More recently, the COMMANDS trial demonstrated superior transfusion independence with luspatercept over erythropoiesis-stimulating agents (ESAs) in ESA-naive, lower-risk MDS patients. However, limited data exist regarding comparative thrombotic risk in real-world MDS populations. We conducted a multicenter, real-world study to evaluate thrombotic event rates associated with luspatercept versus ESAs in MDS patients without prior venous thromboembolism (VTE). Methods: We queried the TriNetX Research Network, a federated real-time electronic health record (EHR) database covering over 100 million patients across major healthcare organizations. Adults (≥18 years) with a diagnosis of MDS (ICD-10-CM code D46) and no prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE) were included. Patients were stratified based on treatment with luspatercept or ESAs (epoetin alfa or darbepoetin alfa). Propensity score matching (PSM) using a 1:1 nearest-neighbor algorithm without replacement was performed to balance demographics and clinical covariates. Primary outcomes included the incidence of DVT, PE, and composite VTE events within 12 months of therapy initiation. Results: A total of 6,448 patients with MDS and no prior VTE were identified: 5,698 received ESAs and 750 received luspatercept. The overall mean age was 72.5 ± 13.5 years, with 48.1% male. After PSM, 741 patients were included in each treatment arm. The matched cohort had a mean age of 76.7 ± 10.7 years, and 41.3% were female. In the ESA group, 58/741 (7.8%) developed DVT compared to 27/741 (3.6%) in the luspatercept group (Hazard Ratio [HR] 1.4; 95% CI, 0.9–2.3). PE occurred in 27 ESA-treated patients (3.6%) versus 13 luspatercept-treated patients (1.8%) (HR 1.3; 95% CI, 0.6–2.7; p=0.941). The overall composite VTE rate was 10.0% (74/741) in the ESA group and 4.9% (36/741) in the luspatercept group (HR 1.3; 95% CI, 0.9–2.0; p=0.732). Conclusion: In this large, multicenter real-world analysis, we observed a numerically lower incidence of thrombotic events with luspatercept compared to erythropoietin-based agents in patients with MDS, though differences did not reach statistical significance. These findings support the thrombotic safety profile of luspatercept observed in clinical trials and warrant further prospective validation.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n=71; hospitalized, n=9, non‐hospitalized, n=62 during the acute infection) and controls (n=50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p=0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n = 71; hospitalized,n = 9,non‐hospitalized,n = 62 during the acute infection) and controls(n = 50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p = 0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.