The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML. Issue 8 (21st June 2019)

• Record Type: Journal Article
• Authors: Dunlap, Jennifer B.; Leonard, Jessica; Rosenberg, Mara; Cook, Rachel; Press, Richard; Fan, Guang; Raess, Philipp W.; Druker, Brian J.; Traer, Elie
• Is Part Of: American journal of hematology. Volume 94:Issue 8(2019:Aug.)
• Page Start: 913
• Page End: 920
• Publication Date: 2019-06-21
• Subjects: Hematology -- Periodicals; 616.15
• DOI: 10.1002/ajh.25517
• Languages: English
• ISSNs: 0361-8609

Abstract

Abstract: Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, ∼30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, ∼40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next‐generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.