Triple Mutation More Deadly in Favorable-Risk AML

Harboring a combination of the NPM1, DNMT3A, and IDH1/2 mutations predicts lower inferior overall survival (OS) in a subset of patients with favorable-risk acute myeloid leukemia, according to the results of a study published in the American Journal of Hematology.

“We sought to investigate factors that predict inferior outcome in a uniformly treated and well-characterized population of patients at our institution,” wrote authors, led by Jennifer B. Dunlap, MD, Department of Pathology, Oregon Health & Science University, Portland, Oregon.

Researchers utilized a targeted next-generation sequencing (NGS) panel developed at Oregon Health & Science University to assess the clearance of mutations after therapy, clonal evolution at relapse, and combinations of mutations. They prioritized mutations that contribute to relapse in 40 FLT3-ITD negative patients with normal cytogenetics and mutated NPM1, who had sequential samples available for analysis. Results of the study were validated using a large publically available genetic dataset with 1,540 AML patients.

The researchers found that mutations in DNMT3A and IDH1/2 were the most common mutations extant in the discovery cohort at the time of diagnosis. In the initial dataset, favorable-risk AML patients with NPM1, DNMT3A, and IDH1/2 mutations demonstrated a trend towards decreased overall survival (OS). Whereas in the validation cohort, a significant difference in OS for patients with all three mutations was observed, with a 5-year OS of only about 30%.

“The survival curves were quite similar between our cohort and this much larger dataset. It is notable that the curves separate 1 to 2 years after initiation of treatment, consistent with relapse after completion of consolidation therapy,” wrote the authors.

Interestingly, the combination of NPM1 plus IDH1/2 mutations, but minus DNMT3A mutations, did not exhibit inferior OS, which indicates that co-mutation patterns are integral in prognosis with respect to IDH1/2 mutations.

On analysis of relative variant allele frequencies, early mutation and expansion of DNMT3A and IDH1/2 before acquisition of NPM1 mutation led to a higher risk of relapse. In non-relapsed patients with the triple combination of mutations, the converse was true.

The results of the current study reflect recent findings that FLT3-ITD mutations are much worse when combined with DNMT3A, and FLT3-ITD has a less negative impact sans additional DNMT3A. These results may also help elucidate some of the conflicting data on DNMT3A as a prognostic marker, because the context of additional mutations must be considered.

The authors floated two hypotheses explaining the inferior overall survival in patients with the triple combination. First, the combination of these mutations is more resistant to chemotherapy. Second, the order of acquisition altered underlying biology. Importantly, these explanations are not mutually exclusive. The early acquisition of IDH1/2 and DNMT3A in an indolent founder clone may result in intrinsic chemoresistance similar to how myelodysplastic syndrome transforms into AML.

“These patients may benefit from allogeneic HSCT in first remission, or from clinical trials with IDH1/2 inhibitors: either concurrently with chemotherapy, Our data further refines the genetic subclassification of AML, which is crucial to better understand the biology of this heterogeneous disease, and to select patients who will benefit from additional therapy,” concluded the authors.