Detection of molecular minimal residual disease (MRD) while a patient with acute myeloid leukemia (AML) is in complete remission is associated with an increased risk of relapse and death. This finding comes from a systematic study published in The New England Journal of Medicine that adds support to the use of targeted sequencing-based detection of MRD to predict the recurrence of AML.
“In this study, gene sequencing and multiparameter flow cytometry each had independent and additive prognostic value with respect to rates of relapse and survival in patients with AML,” wrote the investigators, led by Mojca Jongen-Lavrencic, MD, PhD, from Erasmus University Medical Center, Amsterdam, the Netherlands. “The detection of residual leukemia with both methods is associated with an excessively high probability of relapse (approximately 75%), and the absence of detection of residual disease with both methods is correlated with a relatively low probability of relapse (approximately 25%). Thus, the combined use of sequencing and flow cytometry during complete remission warrants further development and evaluation in clinical practice.”
Although most patients with newly diagnosed AML have morphologic complete remission after treatment with intensive induction chemotherapy, the relapse rate is high, with most relapses occurring within the first 4 years.
The investigators used a genomewide approach to evaluate the persistence of multiple gene mutations and their effect on treatment outcomes. Patients were treated with intensive chemotherapy regimens and attained morphologic complete remission, with a median follow-up exceeding 3 years.
Between 2001 and 2013, samples of bone marrow or peripheral blood were obtained from 482 adult patients with a confirmed diagnosis of previously untreated AML (n=428) or from those who had refractory anemia with excess of blasts, with a score on the Revised International Prognostic Scoring System of >4.5 (n=54). To be included, patients had to be in either complete remission or complete remission with incomplete hematologic recovery after two cycles of induction chemotherapy
At least one mutation was detected in 430 of the 482 patients (89.2%) at diagnosis, and samples were obtained from these patients during remission. Mutations persisted in 51.4% during complete remission and were present at various allele frequencies (range: 0.02 to 47%).
The detection of persistent mutations in DNMT3A, TET2, and ASXL1 (DTA mutations), did not correlate with an increased rate of relapse.
After excluding persistent DTA mutations, 55.4% of patients in whom molecular MRD was detected had a relapse at 4 years, compared with 31.9% of those in whom molecular MRD was not detected (Hazard ratio [HR]: 2.14; P < 0.001). Those with molecular MRD also had a lower rate of relapse-free survival (36.6% vs 58.1%; HR: 1.92; P < 0.001) and a lower overall survival rate (41.9% vs 66.1%; HR: 2.06; P < 0.001) at 4 years than patients without detection of molecular MRD.
On multivariate analysis, persistence of non-DTA mutations during complete remission was a significant independent predictor of 4-year relapse (HR: 1.89; P < 0.001), relapse-free survival (HR: 1.64; P=0.001), and overall survival (HR: 1.64; P=0.003).
In a group of 340 patients, persistent non-DTA mutations were detected only on sequencing in 64 patients and only on flow cytometry in 41 patients.
The 4-year relapse rate was 73.3% among patients in whom both assays were positive, 52.3% among those who had MRD on sequencing but not on flow cytometry, 49.8% among those who had residual disease on flow cytometry but not on sequencing, and 26.7% among those in whom both assays were negative.
In a multivariate analysis, “the combined use of the two assays for the detection of residual disease conferred independent prognostic value with respect to the rates of relapse (P < 0.001), relapse-free (P < 0.001), and overall survival (P=0.003),” the authors observed.
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