DNMT3A Mutations Predict Poorer Outcome in Younger Adults With AML Irrespective of NPM1 Genotype, but Type of Mutation Matters
In a UK study reported in the Journal of Clinical Oncology, Gale et al found that presence of DNMT3A mutations was associated with poorer prognosis in young adults with cytogenetic intermediate-risk acute myeloid leukemia (AML) irrespective of the presence of NPM1 mutation. Poorer outcome was found for DNMT3A R882 and non-R882 missense mutants, but not for truncations. NPM1 mutation alone portends good outcome, but NPM1 and DNMT3A mutations frequently appear together.
Study Details
In the study, diagnostic samples from 914 patients (97% < 60 years old) from two UK Medical Research Council trials conducted between 1988 and 2002 were screened for mutations in DNMT3A exons 13 to 23. Outcomes were evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation).
Outcome by Mutation Status
DNMT3A mutations were identified in 272 patients (30%); of those with mutations, 64% had R882 mutations, 22% had non-R882 missense mutations, and (13%) had truncations or in-frame deletions. DNMT3A mutation was associated with poorer prognosis than wild-type DNMT3A, but the difference was observed only when results were stratified for NPM1 genotype; this finding reflects the high coincidence of the two mutations, with 80% of patients with DNMT3A mutation also harboring NPM1 mutation.
Although a significant effect on relapse risk was not observed for presence of both wild-type NPM1 and DNMT3A mutation, analysis stratified for NPM1 genotype showed that risk for relapse was significantly greater among patients with DNMT3A mutation (hazard ratio [HR] = 1.35, P < .01). Testing for heterogeneity showed no significant difference between NPM1-mutant and NPM1 wild-type patients (P = .4).
Similarly, although a significant effect on overall survival was not observed for presence of both wild-type NPM1 and DNMT3A mutation, analysis stratified for NPM1 genotype showed that overall survival was poorer among patients with DNMT3A mutation (HR = 1.35, P < .01), and testing for heterogeneity showed no significant difference between NPM1-mutant and NPM1 wild-type patients (P = .9).
Analysis according to type of DNMT3A mutation suggested that outcomes were similar and worse vs DNMT3A wild-type for patients with R882 mutation and non-R882 missense mutation and that outcomes in those with truncation were similar to those with wild-type DNMT3A. In particular, 10-year rates of relapse were 51% and 76% among NPM1 wild-type and mutant patients with R882 mutation, 50% and 55% among patients with non-R882 missense mutation, 35% and 40% among those with truncation, and 40% and 58% among those with wild-type DNMT3A.
Ten-year overall survival was 35% and 11% among NPM1 wild-type and mutant patients with R882 mutation, 38% and 21% among patients with non-R882 missense mutation, 57% and 18% among those with truncation, and 50% and 25% among those with wild-type DNMT3A.
The investigators concluded: “These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.”
Rosemary E. Gale, PhD, of University College London Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Leukaemia and Lymphoma Research, UK, and UK Medical Research Council. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
