Mutations Highly Specific for Secondary AML are Associated with Poor Outcomes in ELN Favorable Risk NPM1-mutated AML.

Overview

Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in approximately 30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable risk AML defined by mutant NPM1 remains unclear. In this multicenter study of AML patients (n=233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) compared to those without sMut (15.3 vs. 43.7 months, p=0.002). Importantly, this finding persisted in the ELN 2017-defined favorable risk subset (14.7 months vs. not reached, p<0.0001). Amongst patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (p=0.015) as well as in both the sMut subset (MRD negative: mOS 73.9 months vs. MRD positive: 12.3 months, p=0.0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs. MRD positive: 10.5 months, p=0.009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.