For patients with acute myeloid leukemia (AML), the detection of molecular minimal residual disease (MRD) in patients achieving morphologic complete remission (CR) was associated with a higher risk of relapse and a lower risk of relapse-free survival, according to a study published in The New England Journal of Medicine. Recurrent mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) during a four-year follow-up period, however, did not provide this prognostic value.
“In this study, genetic sequencing and multiparameter flow cytometry each had independent and additive prognostic value with respect to rates of relapse and survival in patients with AML,” the authors, led by Mojk Jongen-Lavrencic, MD, PhD, from Erasmus University Medical Center in Rotterdam, Netherlands, wrote. “The detection of residual leukemia with both methods is associated with an excessively high probability of relapse (approximately 75%).” Conversely, “the absence of [MRD] is correlated with a relatively low probability of relapse (approximately 25%).”
The trial enrolled 482 patients with previously untreated AML or myelodysplastic syndromes involving refractory anemia with excess blasts; all participants were in CR or CR with incomplete hematologic recovery (CRi) and were considered to be at high or very-high risk of relapse (defined as a >4.5 score on the Revised International Prognostic Scoring System).
Patients underwent targeted next-generation sequencing at diagnosis and during CR to detect mutations in 54 genes associated with hematologic malignancies. MRD also was detected using multiparameter flow cytometry.
Nearly 90 percent of patients (n=430) had at least one mutation at diagnosis, and the average number of mutations was 2.9 per patient. The most common of these were mutations in NPM1, DNMT3A, FLT3, and NRAS.
During CR, 51.4 percent of these patients had persistent mutations and “the rate at which mutations persisted was highly variable across genes,” the investigators reported. The most common were mutations in DTA: DNMT3A, TET2, and ASXL1. “The allele frequencies of the mutations that persisted during complete remission ranged from 0.02 to 47 percent,” they added, suggesting “that residual mutation-bearing cells could constitute a minor population of the cells or perhaps even a majority of the cells.”
Over a median follow-up of 40 months (range not reported), detection of any persistent mutation was associated with an increased risk of relapse, compared with no persistent mutations, in a training cohort of 283 patients (4-year relapse rate = 48.2% vs. 32.4%; p=0.03). To account for the presence of age-related clonal hematopoiesis, the investigators excluded mutations in DTA or those with a high allele frequency; however, this had “no clear effect on the relationship between persistent mutations and an increased relapse risk.”
Therefore, after exclusion of persistent DTA mutations, the researchers observed that the detection of molecular MRD, compared with no detection, was associated with:
- higher rates of relapse (55.4% vs. 31.9%; hazard ratio [HR]=2.14; 95% CI 1.57-2.91; p<0.001)
- lower rates of 4-year relapse-free survival (36.6% vs. 58.1%; HR=1.92; 95% CI 1.46-2.54; p<0.001)
- lower rates of 4-year overall survival (41.9% vs. 66.1%, respectively; HR for death = 2.06; 95% CI 1.52-2.79; p<0.001)
Results from the multivariate analysis, which accounted for age, white-cell count, 2017 European Leukemia Network risk classification, and the number of induction chemotherapy cycles required to achieve CR, validated the independent prognostic value of molecular MRD for the following:
- 4-year relapse rates (HR=1.89; 95% CI 1.34-2.65; p<0.001)
- 4-year relapse-free survival (HR=1.64; 95% CI 1.22-2.20; p=0.001)
- 4-year overall survival (HR=1.64; 95% CI 1.18-2.27; p=0.003)
Combining multiparameter flow cytometry with next-generation sequencing to detect molecular MRD also “demonstrated significant additive prognostic value,” according to an analysis conducted in a subgroup of 340 participants. The four-year relapse rate was 73.3 percent for patients who had detectable MRD on both assays, and 52.3 percent among those who had detectable MRD on sequencing but not flow cytometry. A multivariate analysis found that the use of the two combined assays for residual disease detection offered significant independent prognostic value for the three study endpoints (relapse [p<0.001]; relapse-free survival [p<0.001]; and overall survival [p=0.003]).
This study is limited by the median follow-up of only 40 months, which reduces the likelihood of detecting relapses that “generally occur within the first four years” of complete AML remission, Peter J.M. Valk, PhD, told ASH Clinical News.
“Although these are early results, I believe that molecular MRD detection with next-generation sequencing will be implemented in the routine analyses of AML patients during the course of treatment,” he added. “We only looked at a single time point, [so] it will be of great interest to dynamically monitor disease in AML patients and see how the kinetics of disease relate to relapse.”
The corresponding authors report financial relationships with the Netherlands Organization for Scientific Research and the Ministry of Health of the Sultanate of Oman. The study was supported by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and The Netherlands Organization for Health Research and Development.
Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:1189-99.