DNMT3A

The prognostic impact of MRD monitoring of DNTMT3A mutant transcript in AML patients – a German study

DNA methyltransferase 3A (DNMT3A) transcript levels persist in remission and does not impact relapse and survival outcomes in Acute Myeloid Leukemia (AML) patients according to a study published in Leukemia by Verena I. Gaidzik and colleagues from the University of Ulm, Ulm, Germany.

DNMT3A is one of the most frequently mutated genes in AML occurring in approximately 25% of patients. Previous studies have shown that the presence of mutant DNMT3A (DNMT3Amut) predicts for an inferior Overall Survival (OS) and Relapse Free Survival (RFS). However, it is not clear whether there is any prognostic significance of Minimal Residual Disease (MRD) monitoring of DNMT3Amut transcripts in AML patients, hence the rationale for this study.

Gaidzik et al., aimed to investigate whether DNMT3Amut can be used as a molecular marker for MRD monitoring and if it can predict outcomes in AML patients. To do this, the authors analyzed MRD by Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) in 1,494 Peripheral Blood (PB [n = 696]) or Bone Marrow (BM [n = 798]) samples from 181 intensively treated AML patients (median age = 50 years) harboring one of the two DNMT3Amut hot spot mutations, DNMT3A-R882H (n = 126) or DNMT3A-R882C (n = 55) who were enrolled in one of three multicenter treatment trials (NCT00146120, NCT00151242, and NCT00893399) of the German-Austrian AML Study Group (AMLSG).

The key results of the study were:
  • At diagnosis, DNMT3Amut Transcript Levels (TL) did not correlate with clinical characteristics including age (P = 0.76), platelet count (P = 0.22), serum lactate dehydrogenase level (P = 0.26) and BM (P = 0.90) or PB (P = 0.51) count
  • DNMT3Amut TL did not correlate with AML- associated gene mutations at diagnosis including NPM1 (P = 0.33), FLT3-ITD (P = 0.36), FLT3-TKD (P = 0.33) and CEBPA (P = 0.65)
  • DNMT3Amut TL were significantly higher in the BM than in PB after induction cycle I (P = 0.01), induction cycle II (P = 0.05), consolidation I (P = 0.004), and consolidation II (P = 0.008)
  • BM DNMT3Amut TL as log 10 transformed continuous variable during therapy did not impact the rate of death and relapse.
  • DNMT3Amut BM TL were not significantly associated with a higher risk of relapse or shorter OS after two induction cycles and at the end of therapy
  • Only a minority of patients (8/90) achieved DNMT3Amut RQ-PCR negativity in the BM after two cycles of induction
  • At the end of therapy, only four patients were DNMT3Amut RQ-PCR negative in the BM

In summary, most patients had persistent DNMT3Amut transcript levels with only a minority achieving MRD negativity which supports “the concept of clonal hematopoiesis in hematologic remission” according to the authors.

The authors highlighted that their study is the largest study to evaluate the “prognostic impact of MRD monitoring in DNMT3Amut AML patients during therapy and follow-up using sensitive techniques”. Gaidzik et al., concluded their study by suggesting that they would not recommend DNMT3Amut as a target for MRD monitoring in AML patients.

Abstract

We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML) patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative polymerase chain reaction (RQ-PCR) in 1,494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics, concurrent gene mutations as well as the survival endpoints. In Cox regression analyses, bone marrow DNMT3Amut transcript levels (log 10 transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in bone marrow than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004), and consolidation II (P=0.008). With regard to the clinically relevant MRD time-points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the endpoints remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, while most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematologic remission.

References
  1. Gaidzik V. I. et al. DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia. Leukemia. 2017 Jun 23. DOI: 10.1038/leu.2017.200. [Epub ahead of print].