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

Balanced rearrangements involving the KMT2A 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/ KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/ KMT2A rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/ KMT2A 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/ KMT2A rearrangements with material for molecular studies available. Patients with 11q23/ KMT2A rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway ( KRAS , NRAS , and PTPN11 ) in 32% of patients. KRAS mutations occurred more often in patients with t(6;11)(q27;q23)/ KMT2A - AFDN compared with patients with the other 11q23/ KMT2A subsets. Specific gene mutations were too infrequent in patients with specific 11q23/ KMT2A rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/ KMT2A - MLLT3 had better outcomes than patients with other 11q23/ KMT2A rearrangements and those without 11q23/ KMT2A 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/ KMT2A rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.