Molecular minimal residual disease predicts poor outcome in AML
medwireNews: The presence of molecular minimal residual disease, identified by next-generation targeted sequencing, is associated with a significantly increased risk for relapse or death in patients with acute myeloid leukemia (AML), study findings indicate.
However, the researchers found that not all persistent mutations predicted a poor outcome. Mutations in DTA genes, which are typically associated with age-related clonal hematopoiesis (also known as clonal hematopoiesis of indeterminate potential), had no significant impact on prognosis, they report in The New England Journal of Medicine.
David Steensma and Benjamin Ebert (Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA) comment on this phenomenon in an editorial accompanying the study.
“Although the concept of persistent minimal residual disease strikes fear in the hearts of oncologists because of its implications in acute lymphoblastic leukemia and other diseases, assessment for minimal residual disease in AML is more nuanced — one must take into account not only whether a mutation is present after initial therapy but what that mutation is,” they say.
Study author Peter Valk (Erasmus University Medical Center, Rotterdam, the Netherlands) and colleagues used targeted next-generation sequencing to detect mutations in 54 genes commonly associated with hematologic cancers in 482 adults, aged a median of 51 years, with newly diagnosed AML.
The majority (89.2%) of patients had at least one mutation at diagnosis, most commonly in NPM1, DNMT3A, FLT3, and NRAS.
After induction therapy (during complete remission), just over half (51.4%) of patients had persistent mutations at allele frequencies ranging from 0.02% to 47.0%.
The most common persistent mutations were observed in the DTA genes (DNMT3A, TET2, and ASXL1) but Valk and team found that these were not significantly associated with an increased risk for relapse.
“However, the limited follow-up of 40 months does not rule out the possibility that persistent DTA mutations represent an increased risk of relapse at a later time point,” they write.
After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate at 4 years compared with no detection (55.4 vs 31.9%), and with significantly lower rates of relapse-free survival (36.6 vs 58.1%) and overall survival (41.9 vs 66.1%) at this timepoint.
Furthermore, multivariate analyses, adjusted for prognostic factors such as age, white cell count, risk classification, and the number of cycles of induction chemotherapy needed to achieve complete remission, confirmed that the persistence of non-DTA mutations during complete remission was associated with a significantly increased risk for relapse (hazard ratio [HR]=1.89), and significantly worse relapse-free survival (HR for relapse or death=1.64) and overall survival (HR=1.64).
The researchers also compared next-generation sequencing with flow cytometry in a subgroup of 340 patients. The 4-year relapse rates in this analysis were 73.3% when both assays were positive for persistent non-DTA mutations, 52.3% with positive sequencing only, 49.8% with positive flow cytometry only, and 26.7% when both assays were negative, indicating that each technique “had independent and additive prognostic value,” Valk et al remark.
They continue: “Thus, the combined use of sequencing and flow cytometry during complete remission warrants further development and evaluation in clinical practice.”
In their editorial, Steensma and Ebert conclude: “In gaining a further understanding of the genetics of minimal residual disease in patients with AML, we are given the opportunity to refine postremission therapy.”
They add: “Therapeutic targeting of specific mutations that are present during remission could delay or prevent relapse.”
By Laura Cowen
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