DNMT3A,   TET2,  Chromatin Regulation,  NPM1,  FLT3,  IDH1/2

Molecular MRD detection can predict survival and relapse in patients with AML

Targeted molecular minimal residual disease (MRD) detection during complete remission was associated with an increased risk of relapse and reduced survival in patients with acute myeloid leukemia (AML), according to findings of a study by Mojca Jongen-Lavrencic from the Erasmus University Medical Center, Rotterdam, Netherlands, and colleagues, reported in the March 2018 issue of the New England Journal of Medicine.

In this large study, bone marrow or peripheral blood samples from 482 AML patients (median age = 51 years, range, 18–66) who were treated with two cycles of standard induction chemotherapy followed by consolidation in HOVON-SAKK clinical trials were obtained between 2001–2013. At diagnosis and after induction therapy (during morphological complete remission [CR]), targeted next-generation sequencing (NGS) was performed on samples from patients in order to detect mutations in 54 genes that are frequently found in patients with hematologic cancers. The endpoints of the study were 4-year relapse rate, relapse-free survival (RFS) and overall survival (OS). 

At diagnosis, at least one single mutation was detected in 89.2% of patients (430/482). The most common detectable mutations at diagnosis include NPM1, DNMT3A, FLT3, and NRAS. The 430 patients in whom at least one mutation was detected at diagnosis were randomly assigned to either a training cohort (n = 283) or a validation cohort (n = 147).

After induction therapy, persistent mutations remained in 51.4% of patients in CR (n = 430) at various allele frequencies (range, 0.02–47%). Most common persistent mutations include DTA mutations including DNMT3A (78.7%), TET2 (54.2%) and ASXL1 (51.6%). Contrarily, the majority of mutations in NRAS, PTPN11, KIT, and KRAS were cleared after induction therapy. The researchers noted that “because DTA mutations have been established as the most common gene mutations in persons with age-related clonal hematopoiesis, the persistent DTA mutations might have represented non-leukemic clones that repopulated the bone marrow after induction therapy”. It was observed that persisting DTA mutations did not associate with an increased incidence of relapse.

In the training cohort, detection of any persistent mutation during CR was associated with an increased risk of relapse (4-year relapse rate, 48.2% with detection vs 32.4% with no detection; P = 0.03). Furthermore, among patients who had persistent DTA mutations during CR, coexisting persistent non-DTA mutations led to an increased relapse rate (4-year relapse rate, 66.7% with detection vs 39.4% with no detection; P = 0.002).

The detection of persistent non-DTA mutations at any allele frequency was strongly associated with an increased relapse risk (4-year relapse rate, 55.7% with detection vs 34.6% with no detection; P = 0.001), reduced RFS (4-year rate of RFS, 56.7% with detection vs 36.6% with no detection; P = 0.006) and OS (4-year rate of OS, 65.3% with detection vs 43.7% with no detection; P = 0.01). These findings were confirmed significantly in the validation cohort.

In the combined training and validation cohorts (n = 430), persistent non-DTA mutations were detected during complete remission in 28.4% of the patients. Non-DTA mutations associated significantly with a higher 4-year relapse rate than no detection (55.4% vs 31.9%, HR = 2.14, 95% CI, 1.57–2.91, P < 0.001), lower 4-year RFS (36.6% vs 58.1%, HR for relapse or death = 1.92, 95% CI, 1.42–2.54 P < 0.001) and OS (41.9% vs 66.1%; HR for death, 2.06, 95% CI, 1.52–2.79, P < 0.001).

In an accompanying editorial published in the same issue of the New England Journal of Medicine, David P. Steensma and Benjamin L. Ebert, both from the Dana-Farber Cancer Institute, Boston, MA, commented on the findings of the study. The authors said that “in gaining a further understanding of the genetics of minimal residual disease in patients with AML, we are given the opportunity to refine post-remission therapy”. They further suggested that “therapeutic targeting of specific mutations that are present during remission could delay or prevent relapse”. David P. Steensma and Benjamin L. Ebert concluded with the following remark “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. In some cases, as Dante pointed out, the devil is not so black as he is painted.”

References
  1. Jongen-Lavrencic M. et al. Molecular Minimal Residual Disease in Acute Myeloid Leukemia. N Engl J Med. 2018 Mar 29; 378(13): 1189–1199. DOI: 10.1056/NEJMoa1716863.
  2. Steensma D. P. & Ebert B. L. Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia. N Engl J Med. 2018 Mar 29; 378(13): 1244–1245. DOI: 10.1056/NEJMe1802610.