DNMT3A Mutation May Add Prognostic Value To Patients With Acute Myeloid Leukemia Of Intermediate Cytogenetic Risk Harboring a Favorable Genetic Profile Of NPM1, FLT3-ITD and CEBPA

Prognostic heterogeneity of AML with intermediate-risk cytogenetics (AML-IR) is mostly clarified by determination of mutations of NPM1 gene (NPM1mut), internal tandem duplication of FLT3 gene (FLT3-ITD), and biallelic mutation of CEBPA (CEBPAmut). Moreover, intrinsic characteristics of these mutations such as allelic burden of FLT3-ITD and additional gene lesions described in this population might provide a refined prognostic categorization and guide postremission strategy. In this context, we analyzed the associated features of DNMT3A mutations (DNMT3Amut) and their prognostic impact and interaction with major molecular categories in patients with AML-IR. Overall, 120 patients (52% male; median age: 51, range: 18-71) diagnosed with de novo AML-IR (MRC definition) in the cooperative group CETLAM between 1994 and 2013 who received intensive AML chemotherapy were included in the analysis. DNMT3Amut were analyzed by RT-PCR and Sanger sequencing as previously described, and were found in 44 patients (37%), 25 (57%) with a mutation in the R882 position. NPM1 and FLT3-ITD were analyzed in all patients, and CEBPA in 53. Patients with DNMT3Amut were older (53 vs. 48.5 years, p=0.019), had a higher leucocyte count at diagnosis (median value: 32.85 vs. 16.3x10⁹/L, p=0.019), and showed a trend to an association with FLT3-ITD (p=0.081) compared to patients with wild-type DNMT3A (DNMT3Awt). For survival analysis, only patients up to 60 years old were analyzed. For a deeper insight on the interaction of DNMT3A with other mutations, we grouped patients in two different molecular categories according to presence of NPM1mut, FLT3-ITD, and CEBPA, as well as FLT3-ITD/wt ratio (based on a previous analysis detailed in Pratcorona M, Blood 2013, 121(14):2734-8). Thus, we distinguished two molecular categories: 1) a favorable molecular subgroup (n=39): NPM1mut without FLT3-ITD or a low ratio ITD/wt ratio, <0.5; and patients with CEBPAmut, 2) unfavorable molecular subgroup (n=56), consisting of patients lacking both NPM1mut and CEBPAmut and/or harboring FLT3-ITD (with a ratio >0.5 for concomitant NPM1mut). In the overall series, complete response rate (CR), survival (OS), and leukemia free survival (LFS) were 84%, 43±5% (5-yr), and 38±5% (5-yr), respectively. There was no effect of DNMT3A in the global series. Nonetheless, outcome of patients with DNMT3A from the favorable subgroup was significantly worse, with an inferior 5-year OS and LFS (40±14% vs 76±8%, p=0.029; 35±14% vs 71±9%, p=0.031). On the contrary, DNMT3A mutations did not confer a different outcome in other molecular subgroups.

Of note, patients with DNMT3Amut showed a trend for a better OS after receiving an allogeneic stem cell transplantation after first CR (OS at 5 years 37±12 vs 78±14, p=0.122) (Figure 2).

Identification of the prognostic value of DNMT3A in the favorable molecular group might be of relevance, since general guidelines do not recommend allogeneic stem cell transplantation in first CR in this group. Based on this finding, this recommendation may be reconsidered in cases with DNMT3Amut, but larger studies are warranted to confirm it.