Technical Validation and Prospective Clinical Utility of Optical Genome Mapping in Acute Leukemia Workup: Insights...

In November 2023, our Canadian tertiary care facility implemented optical genome mapping (OGM) as a first-line diagnostic test for adults with newly diagnosed acute leukemias. Here, the analytical performance and clinical utility of OGM alongside karyotype, fluorescence in situ hybridization (FISH), and next-generation sequencing are reported. During test validation, OGM demonstrated robust analytical performance, reproducibility, and limits of detection, revealing 100% specificity, 96.1% sensitivity, and 98.0% accuracy. After implementation, clinical reports from the entire cytogenetic and molecular genetic workflow were prospectively compiled from the first 200 cases to evaluate concordance with parallel karyotype/FISH and added yield of OGM. A total of 640 reportable variants were detected by OGM and stratified on the basis of clinical significance, classified as tier 1A (25%), tier 1B (3%), tier 2 (2%), or tier 3A (70%). Of these, 64 variants were missed by karyotype and FISH, 3 KMT2A partial tandem duplications were missed by next-generation sequencing, and 9 cases with failed karyotype were rescued by OGM: overall impacting 35 cases (18%) by altering diagnostic classification (n = 12) and/or risk stratification (n = 31). Despite comprehensive pre-existing diagnostic workflows, implementation of OGM has revealed diagnostically and prognostically significant alterations in cases otherwise cryptic or failed by karyotype, demonstrating strong clinical utility and supporting its use as a first-tier diagnostic test for hematolymphoid malignancies.