Point Mutations in the -ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant -PTD

-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the JMD were identified with a prevalence of ~1.23% (n = 19). Both -ITD and non-ITD mutations were associated with a higher rate of (42%-61%; < 0.001) and mutations (37%-43%; < 0.001), as well as an increased percentage of peripheral blood (54%-65%) and bone marrow blast cells (74%; < 0.001), compared to -wild-type patients. Most significantly, AML patients with non-ITD mutations had a higher rate of concomitant -PTD mutations (37.5%; < 0.001) as compared to -ITD (7%) or -wild-type cases (4.5%). In a multivariable analysis, non-ITD mutations were not an independent prognostic factor. However, patients with dual non-ITD and -PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML.