MRD Prognostic of Poorer Outcomes in AML

Molecular minimal residual disease (MRD) was associated with a higher rate of relapse and a lower rate of relapse-free survival (RFS) and overall survival (OS) for patients with newly-diagnosed acute myeloid leukemia (AML), according to findings published in the New England Journal of Medicine.

Researchers obtained samples between 2001 and 2013 of bone marrow or peripheral blood from 482 patients with previously untreated AML (n =428) or refractory anemia with excess of blasts. Patients had to be in either complete remission (CR) or CR remission with incomplete hematologic recovery with less than 5% blast cells in the bone marrow after receiving 2 cycles of induction chemotherapy.

The investigators used next-generation sequencing at diagnosis to detect mutations which could potentially serve as a marker of residual disease. Next-generation sequencing was conducted using the Illumina TruSight Myeloid Sequencing Panel (Illumina) to detect mutations in 54 genes commonly found in patients with hematologic cancers. At least 1 such mutation was present in 430 patients (89.2%).

The most common detectable mutations at diagnosis were NPM1, DNMT3A, FLT3, and NRAS. DTA mutations were most common, persisting at rates of 78.7% for DNMT3A, 54.2% for TET2, and 51.6% for ASXL1. In contrast, the majority of mutations in NRAS, PTPN11, KIT, and KRAS were cleared after induction therapy.

Compared with no detection, the detection of molecular MRD was associated with a significantly higher relapse rate (55.4% vs 31.9%; HR, 2.14; P <.001) and lower rates of RFS (36.6% vs 58.1%; HR for relapse or death, 1.92; P <.001) and OS (41.9% vs 66.1%; HR for death, 2.06; P <.001).

“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,” corresponding author Peter J.M. Valk, PhD, Erasmus University Medical Center, department of hematology, Rotterdam, the Netherlands, and colleagues wrote.

“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,” added Valk et al.

The 430 patients who were positive for at least 1 mutation, were randomly assigned to either a training cohort (n = 283) or a validation cohort (n = 147). In the training cohort, the detection of any persistent mutation during CR was associated with an increased risk for relapse. At 4 years, relapse rate was 48.2% with detection compared with 32.4% with no detection (P = .03). Investigators found that the correlation of persistent mutations with an increased relapse risk appeared to be independent of allele frequency.

Detection of persistent DTA mutations was not significantly associated with a higher 4-year relapse rate compared with no detection (P = .29). The absence of a correlation was independent of allele frequency.

In contrast, among patients who had persistent DTA mutations during CR, coexisting persistent non-DTA mutations had high prognostic value with 4-year relapse (66.7% with detection vs. 39.4% with no detection; P = .002).

“Thus, in patients with persistent DTA mutations, the presence of residual disease that specifically included coexisting non-DTA mutations represented a predictor of impending relapse,” Valk et al wrote.

In multivariate analysis, sequencing-based detection of non-DTA mutations maintained significant independent prognostic value for relapse (HR, 1.89; 95% CI, 1.34-2.65; P <.001), RFS (HR, 1.64; 95% CI, 1.22-2.20; P = .001), and OS (HR, 1.64; 95% CI, 1.18-2.27; P = .003). There were no significant interactions observed between the detection of residual disease and the other prognostic factors in the multivariate model, type of consolidation therapy, or disease entity (AML vs. refractory anemia with excess of blasts).

Jongen-Lavrencic M, Grob T, Hanekamp K, et al. Molecular minimal residual disease in acute myeloid leukemia [published online March 29, 2018]. N Engl J Med. 2018; 378:1189-1199. doi: 10.1056/NEJMoa1716863.