Effect of DNMT3A variant allele frequency and double mutation on clinicopathologic features of patients with de novo AML.

Blood Advances
Damodaran NarayananOlga K Weinberg

Abstract

The clinicopathologic features of DNA methyltransferase 3A (DNMT3A)-mutated de novo acute myeloid leukemia (AML), and the significance of variant type, variant allele frequency (VAF), and multiple concomitant DNMT3A mutations, remain poorly defined. We examined 104 DNMT3A-mutated de novo AML patients from 2 major centers. Most (82%) had normal karyotype (NK); R882H variants were frequent(38%). The most commonly comutated genes included nucleophosmin (NPM1; 53%), Fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (25%), IDH1 (23%), IDH2 (23%), and TET2 (21%). Patients with high DNMT3A VAF at diagnosis (≥44%; DNMT3AHIGH) had more significant leukocytosis and higher blast counts in peripheral blood and bone marrow. DNMT3AHIGH cases were associated with much shorter event-free survival (EFS; 14.1 vs 56.8 months) and overall survival (OS; 18.3 months vs not reached) compared with cases of patients with low DNMT3A (DNMT3ALOW). Thirteen patients had 2 DNMT3A variants and similar VAFs at diagnosis that tracked together at multiple time points after chemotherapy and/or stem cell transplantation (SCT). In multivariable analyses performed in NK patients who received standard induction chemotherapy, presence of 2 DNMT3A mutat...Continue Reading

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