Real-world evidence for comprehensive genomic profiling in myeloid malignancies: Changes in detection and clinical impact.

e18636 Background: Myeloid malignancies are characterized by marked genomic heterogeneity, where accurate and timely identification of pathogenic and actionable alterations is essential for diagnosis, prognostication, and therapeutic decision making. Targeted gene panels remain widely used but may miss clinically relevant variants. Comprehensive genomic profiling (CGP) offers broader molecular coverage, yet its real-world impact in myeloid disease is not well defined. Methods: In a retrospective study, molecular profiles of 6,481 patients were analyzed by integrating Neogenomics sequencing data (01/2025 – 12/2025) with standardized clinical data (cancer diagnoses, ICD-10 codes, medication records, molecular testing results) extracted from comprehensive electronic medical records using the xCures platform. Results: Pathogenic or likely pathogenic (P/LP) variants were detected in 2,763 of 5,610 patients with abnormal or detected results. The most tested assays included the NEO Comprehensive Myeloid (n=1,406) and NEO Comprehensive Heme (n=467) panels, as well as the NeoTYPE MDS/CMML Profile (n=698), NeoTYPE AML Prognostic Profile (n=76), and NEO AML Express (n=39). Medical record review of 1,066 patients with P/LP variants demonstrated that 199 received targeted therapy, with 50 initiating treatments within 30 days and 58 within 60 days of testing at Neogenomics. Targetable pathogenic variants (FLT3, IDH1, IDH2, and JAK2) were identified in 12 patients receiving targeted therapy (midostaurin, ivosidenib, enasidenib, ruxolitinib) within 60 days of Neo test results, 83% of whom were tested using the NEO Comprehensive Myeloid or Heme panels. Among 813 patients with initially unspecified diagnoses, 584 (72%) received definitive diagnoses within 30 days of CGP, and 74% of these were evaluated using the NEO Comprehensive panels. Conclusions: CGP markedly enhanced the detection of pathogenic and actionable variants beyond what targeted panels captured, translating into meaningful clinical impact. In this real-world cohort, CGP enabled definitive diagnoses in majority of previously unspecified cases. These findings demonstrate that broader molecular coverage not only improves diagnostic precision but also accelerates therapeutic decision-making, underscoring CGP as a critical tool for precision medicine in myeloid malignancies.