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Background CD8 + T-cells often predict better outcomes in solid tumors, but their role in AML is unclear. In CN-AML, we used transcriptomic data to assess the prognostic relevance of CD8+ infiltration and its association with immune-exhaustion and stromal-features in leukemic microenvironment.Methods Transcriptomic data (GSE71014) from 104 pre-treatment CN-AML bone-marrow samples were analyzed. Gene expression data was normalized and annotated using GPL10558. Immune and stromal cell infiltration scores were estimated with MCP-counter-style approach. CD8 and exhaustion scores were calculated from mean expression of selected marker genes. Patients were separated into CD8-high and CD8-low groups by median CD8-score. Overall survival (OS) was compared using Kaplan-Meier curves and log-rank tests. Univariable and multivariable Cox models were used for prognostic associations. Gene Set Enrichment Analysis (GSEA) using Hallmark gene-sets were used to compare groups, and Spearman correlation (r) was used to evaluate relationships between immune and stromal features.Results Higher CD8 + T-cell and endothelial-infiltration were associated with reduced long-term OS. CD8-high patients had 1, 3, 5, and 10-year OS rates of 80.1%, 56.3%, 50.0%, and 42.9%, compared to 73.1%, 64.5%, 64.5%, and 56.4% in the CD8-low group (p<0.005). Endothelial-high patients exhibited early attrition, with survival decreasing from 70.1% at 1 year to 38.0% at year 5 and 32.6% at year 9, the latest available follow-up. Endothelial-low patients showed more favorable survival of 83.1%, 77.1%, 77.1%, and 67.5% at 1-3-5-10-year time-periods. High-exhaustion-scores were linked to declining OS from 75.4% at 1-year to 37.8% at 9-years, compared to 75.0% and 59.3% in low-exhaustion patients (figure 1), though differences weren’t statistically significant. In multivariable-analysis, CD8 and exhaustion-scores weren’t prognostic, though LAG3 showed borderline-association with worse-OS (Hazard Ratio (HR)=1.34, p=0.08). CD8-high samples showed enrichment of TNF-α via NF-κB (Normalized Enrichment Score (NES)=3.47, FDR q<0.001), IFN-γ response (NES=2.90), and IL6-JAK-STAT3 signaling (NES=2.14). Expression of PDCD1, IFNG, and GZMB were significantly higher (all p<0.005), indicating immune activation but also dysfunction. CD8+ T-cells correlated with total T-cells (r=0.89), monocytic-lineage (r=0.23), and endothelial cells (r=0.30). Patients with higher endothelial infiltration had worse overall survival (HR=1.78; p < 0.05). The model showed moderate accuracy (concordance=0.61; Akaike-Information-Criterion=292.4). CD8 and endothelial scores were only weakly related (r = 0.18), suggesting they may reflect different biological features.Conclusions In CN-AML, higher CD8 + T cell and endothelial infiltration were associated with reduced overall survival. Despite signs of immune activation, poor outcomes in CD8-high cases suggest immune dysfunction. These results highlight the need to target exhaustion and stromal pathways in AML.Abstract 834 Figure 1Kaplan-Meier survival curves comparing overall survival by CD8+ T cell infiltration (left), endothelial cell infiltration (center), and immune exhaustion score (right) in patients with cytogenetically normal AML