Optical genome mapping detects cryptic high-risk and targetable abnormalities in adult AML

Acute myeloid leukaemia (AML) risk stratification relies on cytogenetic and molecular abnormalities defined by European LeukemiaNet (ELN) 2022. Conventional cytogenetic techniques, including chromosomal banding analysis (CBA) and fluorescence in situ hybridization, have limited resolution and may miss cryptic events. Optical genome mapping (OGM) is a genome-wide approach capable of detecting balanced and unbalanced structural variants with high resolution, potentially revealing cryptic abnormalities of diagnostic and prognostic relevance. We retrospectively studied 100 adults with newly diagnosed AML, each showing one to two cytogenetic abnormalities and lacking the World Health Organization 2022-defining rearrangements or baseline ELN adverse karyotypes. OGM was performed to evaluate additional cytogenetic abnormalities and impact on ELN 2022 risk classification. Clinical outcomes were explored descriptively. OGM detected 91.4% of abnormalities identified by CBA and provided additional information in 37% (95% confidence interval: 28%-47%) of patients. Fourteen per cent was reclassified to an unfavourable cytogenetic group, and 7.7% was reclassified to ELN 2022 adverse risk. Cryptic KMT2A and NUP98 lesions were found in 10% of cases, highlighting potential therapeutic targets. Survival analyses suggested a trend towards poorer outcomes in patients reclassified as adverse, though the small sample limits definitive conclusions. In low-complexity AML, OGM provides substantial incremental diagnostic value, detecting cryptic high-risk and targetable abnormalities, supporting its use as a complementary tool.