Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/ <i>KMT2A</i>

Abstract

Balanced rearrangements involving the <i>KMT2A</i> gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/<i>KMT2A</i> rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/<i>KMT2A</i> rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/<i>KMT2A</i> rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/<i>KMT2A</i> rearrangements with material for molecular studies available. Patients with 11q23/<i>KMT2A</i> rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (<i>KRAS</i>, <i>NRAS</i>, and <i>PTPN11</i>) in 32% of patients. <i>KRAS</i> mutations occurred more often in patients with t(6;11)(q27;q23)/<i>KMT2A</i>-<i>AFDN</i> compared with patients with the other 11q23/<i>KMT2A</i> subsets. Specific gene mutations were too infrequent in patients with specific 11q23/<i>KMT2A</i> rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/<i>KMT2A</i>-<i>MLLT3</i> had better outcomes than patients with other 11q23/<i>KMT2A</i> rearrangements and those without 11q23/<i>KMT2A</i> rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/<i>KMT2A</i> rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.