A Systematic, Evidence-Based Workflow for Classifying KMT2A Fusions in AML.

KMT2A fusions are a critical oncogenic driver in 5-10% of acute myeloid leukemia (AML) patients and are associated with poor prognosis. Currently, there are no published somatic guidelines for fusions in AML and developing methods to accurately classify fusions, especially those involving KMT2A, is essential for patient care. Therefore, the LabPMM KMT2A Fusions Workflow was developed to address this need. This workflow was designed based on the somatic guidelines by Horak et al., where classification of oncogenicity is based on points awarded for varying types of evidence. Fusions previously detected by LabPMM's CAP/CLIA-certified MyAML and MyMRD gene panels were used to test this workflow. A total of 100 KMT2A fusions were reassessed and 97 of these had a breakpoint in the major breakpoint cluster region (BCR1). There were 20 distinct partner genes for KMT2A with various functions and the most common partners were MLLT3, ELL, AFDN, MLLT10, and AFF1. Five KMT2A fusions had a novel partner (MYB, RC3H1, SNAPC3, STPG1, and HPSE2). Breakpoints in the partner genes were assessed to better understand their potential role in driving leukemogenesis. Out of the 100 fusions reassessed, 9 had a classification change. This LabPMM KMT2A Fusions Workflow provides a points-based system for curation that allows for standardization and clarity both within and among genetic diagnostic laboratories reporting on KMT2A fusions in AML.