Characterizing KMT2A Rearrangement in Acute Myeloid Leukemia: A Comprehensive Genomic Study

<b>Background</b>: The <i>KMT2A</i> (<i>MLL1</i>) gene is altered in a variety of hematological malignancies and solid tumors. <i>KMT2A</i>-rearranged (<i>KMT2Ar</i>) AML represents a distinct subtype associated with poor outcomes and high relapse rate despite initial responsiveness to chemotherapy. <b>Methods</b>: A total of 3863 cases of AML peripheral blood samples were analyzed using the FoundationOne Heme combined comprehensive hybrid capture-based DNA and RNA sequencing assay. <b>Results</b>: Of the 3863 AML cases, 521 (13.4%) featured genomic alterations (GAs) in the <i>KMT2A</i> gene, 99.1% of which were large rearrangements (<i>KMT2Ar</i>). A total of 56.9% were males with a median age of 62 years. Of the <i>KMT2Ar</i> cases, there were 43.1% <i>KMT2A</i> duplications, 52.7% fusions, and 4.2% not otherwise specified rearrangements. A total of 0.9% of the <i>KMT2A</i>-altered AML cases were short variant mutations. There were no <i>KMT2A</i> (0%) amplifications or deletions. <i>KMT2Ar</i> cases were associated with increased GA frequencies in <i>FLT3</i> (27.3% vs. 19.8%; <i>p</i> = 0.0002), <i>KRAS</i> (17.2% vs. 7.8%; <i>p</i> < 0.0001) (overall; 1.1% <i>KRAS</i> G12C), and <i>IDH2</i> (16.0% vs. 10.4%; <i>p</i> < 0.0001), while <i>KMT2A</i> wild-type AML (<i>KMT2Awt)</i> had significantly increased GA frequencies in <i>RUNX1</i> (20.7% vs. 15.8%; <i>p</i> = 0.0081), <i>ASXL1</i> (16.6% vs. 10.5%; <i>p</i> = 0.0003), and <i>TET2</i> (16.4% vs. 10.1%; <i>p</i> = 0.0002), <i>NPM1</i> (17.5% vs. 0.2%; <i>p</i> < 0.0001), and <i>TP53</i> (17.8% vs. 7.9%; <i>p</i> < 0.0001). <b>Conclusions</b>: <i>KMT2A</i> rearrangements are common in AML (13.4% of cases featured <i>KMT2Ar</i>). A total of 99.1% of alterations in <i>KMT2A</i> are large rearrangements, with fusions being the most commonly observed alteration (52.7% of total rearrangements). No amplifications or deletions were seen. This genomic landscape study highlights significant genomic differences between <i>KMT2Ar</i> and <i>KMT2Awt</i> AML patients, which may enrich our understanding of the molecular profile and clusters of mutations in AML.