Prognostic impact of KMT2A-PTD in acute myeloid leukemia in the NGS era: a multicenter retrospective study

The KMT2A gene is frequently altered in acute myeloid leukemia (AML). KMT2A abnormalities include partial tandem duplication (PTD), single-nucleotide variants (SNVs), and chromosomal rearrangements such as t(9;11)(p21.3;q23.3) and t(v;11q23.3). However, with the widespread adoption of next-generation sequencing (NGS), PTD has been assessed less frequently. We evaluated the clinical features and prognostic impact of PTD and other KMT2A abnormalities. We analyzed the KMT2A abnormalities and coexisting genetic alterations in 585 patients with de novo AML diagnosed across 25 institutions (1991-2020). Using bone marrow and/or peripheral blood samples, we identified PTD by targeted polymerase chain reaction-based assay, chromosomal rearrangements by karyotyping, and SNVs and other genetic alterations by targeted NGS. KMT2A abnormalities were detected in 18.3% of de novo AML, comprising PTD in 6.7%, SNVs in 5.1%, t(9;11)(p21.3;q23.3) in 2.2%, and t(v;11q23.3) in 4.8%; 0.5% had concurrent KMT2A abnormalities. Patients with PTD, t(9;11)(p21.3;q23.3), or t(v;11q23.3) had significantly shorter relapse-free survival (RFS) than the KMT2A wild-type group (hazard ratio [HR] 1.99, p = 0.048; HR 3.13, p = 0.009; HR 2.41, p = 0.006, respectively). Patients with PTD, t(9;11)(p21.3;q23.3), or t(v;11q23.3) had significantly shorter overall survival (OS) than the KMT2A wild-type group (HR 3.92, p < 0.001; HR 4.58, p < 0.001; HR 3.73, p < 0.001, respectively). Within the PTD group, older age (p = 0.030) and higher lactate dehydrogenase (p = 0.005) remained independent adverse prognostic factors. KMT2A-PTD is associated with inferior RFS and OS in de novo AML. Our findings support routine PTD testing at diagnosis and the incorporation of KMT2A-PTD into prognostic risk stratification and clinical decision-making.