The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML

Jennifer Dunlap, Jessica Leonard, Mara Rosenberg, Rachel Cook, Richard Press, Guang Fan, Phil Raess, Brian Druker, Elie Traer

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)913-920
Number of pages8
JournalAmerican Journal of Hematology
Volume94
Issue number8
DOIs
StatePublished - Aug 1 2019

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Acute Myeloid Leukemia
Mutation
Survival
Recurrence
Insertional Mutagenesis
Gene Frequency
Chromosome Aberrations
Stem Cells
Clinical Trials
Transplants
Genes

ASJC Scopus subject areas

  • Hematology

Cite this

The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML. / Dunlap, Jennifer; Leonard, Jessica; Rosenberg, Mara; Cook, Rachel; Press, Richard; Fan, Guang; Raess, Phil; Druker, Brian; Traer, Elie.

In: American Journal of Hematology, Vol. 94, No. 8, 01.08.2019, p. 913-920.

Research output: Contribution to journalArticle

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AU - Press, Richard

AU - Fan, Guang

AU - Raess, Phil

AU - Druker, Brian

AU - Traer, Elie

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