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

Abstract

Balanced rearrangements involving theKMT2Agene, 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/KMT2Arearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/KMT2Arearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/KMT2Arearrangement 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/KMT2Arearrangements with material for molecular studies available. Patients with 11q23/KMT2Arearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (KRAS,NRAS, andPTPN11) in 32% of patients.KRASmutations occurred more often in patients with t(6;11)(q27;q23)/KMT2A-AFDNcompared with patients with the other 11q23/KMT2Asubsets. Specific gene mutations were too infrequent in patients with specific 11q23/KMT2Arearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/KMT2A-MLLT3had better outcomes than patients with other 11q23/KMT2Arearrangements and those without 11q23/KMT2Arearrangements 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/KMT2Arearrangement have distinct mutational patterns and outcomes depending on the fusion partner.