Institution: | 1. Department of Pathology, Oregon Health & Science University, Portland, Oregon;2. Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon;3. Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon;4. Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon
Howard Hughes Medical Institute, Chevy Chase, Maryland |
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. |