Can DNMT3AR882H be used as a marker for MRD monitoring?

It has been reported that the recurrently mutated DNMT3A can be detected in cells of Acute Myeloid Leukemia (AML) patients in long-lasting Complete Remission (CR).¹ In order to investigate whether DNMT3A could be used as a marker for Measurable Residual Disease (MRD) monitoring, Tiziana Ottone from Tor Vergata University, Rome, IT, and colleagues performed a sequential monitoring of DNMT3A^R882H in AML patients and compared it to NPM1-mutation (mutation A) levels. The results of the study were reported in a Correspondence to the American Journal of Hematology.²

Mutational analysis of the most common alteration found in mutated DNMT3A gene, located at residue R882 of the methyltransferase domain (DNMT3A^R882), NPM1 and FLT3 (ITD/TKD) was assessed at diagnosis in 556 patients with de novo AML (median age = 49 years, range 16–89 years) who were enrolled in clinical trials conducted by the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) between 2012–2015.

Quantitative assessment of DNMT3A^R882H, NPM1^mutA and patient-specific FLT3-ITD was performed on bone marrow (BM) samples collected at diagnosis, during follow-up and at the time of relapse

Key findings:

• NPM1^mut transcript levels in patients (n = 51) were significantly different at diagnosis, post-induction and post-consolidation therapy and was independent from DNMT3A^R882 and FLT3 status
• DNMT3A^R882H expression levels, analyzed longitudinally in patients (n = 21) significantly decreased only after induction, but not after consolidation therapy regardless of the presence of FLT3 mutations
• Compared to NPM1^mut, DNMT3A^R882H did not significantly increase at relapse, P = 0.09
• In CR patients, there was no significant difference in DNMT3A^R882H expression between multiparametric flow cytometry (MPFC) MRD positive and negative BM samples
• Compared to NPM1^mut, DNMT3A^R882H expression levels in patient cells at relapse were higher in total BM-mononuclear cells than in the leukemia associated immunophenotype positive cells

The authors concluded by stating that their study “indicates that DNMT3A^R882H quantification is an unreliable tool for MRD monitoring since it does not reflect disease status in AML”. They further added that “DNMT3A^R882H mutation is likely present in pre-leukemic clonal myeloid and lymphoid populations persisting at the time of CR”.