In AML Patients Allografted in First Remission, DNMT3A Mutations Differentially Affect Post-Transplant Outcomes According to Karyotype, NPM1 and FLT3-ITD Mutation Status - from the EBMT-ALWP
Authors: Abou Dalle Iman , Galimard Jacques-Emmanuel , Poiré Xavier , Sanz Jaime , Huynh Anne , Kröger Nicolaus , Wagner Drouet Eva-Maria , Burns David , Eder Matthias , Lioure Bruno , Wu Depei , Mayer Jiri , Carlson Kristina , Stelljes Matthias , Collin Matthew , Aljurf Mahmoud , Nagler Arnon , Esteve Jordi , Ciceri Fabio , Bazarbachi Ali , Mohty Mohamad 
Published: December 2024

Mutations in the DNMT3A gene are commonly found in cytogenetically normal acute myeloid leukemia (AML) and often co-occur with NPM1 mutations and internal tandem duplication (ITD) of the FLT3 gene. However, DNMT3A mutation is not classified as a distinct prognostic group in the latest European LeukemiaNet (ELN) 2022 genetic risk classification of AML. The prognostic significance of the DNMT3A mutation in the context of allogeneic hematopoietic cell transplantation (allo-HCT) remains underexplored. Using a large dataset from the European Society for Blood and Marrow Transplantation (EBMT) registry, we examined the impact of DNMT3A mutations, according to the karyotype, and NPM1 and FLT3-ITD mutation status, on post-transplant outcomes in adult AML patients receiving allo-HCT in first complete remission (CR1). Patients with favorable ELN 2022 cytogenetics were excluded.

We analyzed 1888 adult AML patients (51% female, median age 57 years; range 18-78 years) with ELN 2022 intermediate- or poor-risk cytogenetics and known DNMT3A, FLT3-ITD and NPM1 mutation status, who received their first allo-HCT in CR1 between 2015 and 2022. Of these, 862 (46%) patients had DNMT3Amutation. Those with DNMT3A mutations were less likely to have a secondary AML (14% versus (vs.) 24%, p&lt;0.001) or poor-risk karyotype (9% vs. 25%, p&lt;0.001), but more likely to be female (57% vs. 46%, p&lt;0.001), have normal cytogenetics (75% vs. 52%, p&lt;0.001), FLT3-ITD co-mutation (51% vs. 25%, p&lt;0.001), NPM1 co-mutation (59% vs. 19%, p&lt;0.001), and to receive a myeloablative conditioning and in vivo T cell depletion. Outcome analysis was stratified by baseline karyotype (normal or abnormal).

In the cohort of 1177 patients with normal cytogenetics, 645 (55%) patients had DNMT3A mutations. After a median follow up of 2 years, the 2-year relapse incidence (RI), leukemia-free survival (LFS), and overall survival (OS) was 23%, 63% and 70% respectively, for patients with DNMT3A mutations, compared to 18%, 68% and 74% for those without such mutations. Multivariable analyses (MVA) were conducted within four groups based on FLT3-ITD and NPM1 mutations. Among 444 patients with both FLT3-ITD and NPM1mutations, 340 were triple-positive (77%); there were no significant differences in 2-year RI (25% vs. 24%, hazard ratio [HR]: 1.02, p= 0.95), LFS (61% vs. 64%, HR: 1.1, p=0.67) or OS (70% vs. 76%, HR: 1.56, p=0.11) with and without DNMT3A mutations. Conversely, among 167 patients with NPM1 mutation without FLT3-ITD, the 2-year RI was 17% for 106 patients with DNMT3A mutations and 8% for those without (HR 2.77: p=0.05), leading to significantly lower 2-year LFS (70% vs. 90%, HR: 3.3, p=0.006), but OS was not significantly different (80% vs. 90%, HR: 2.5, p=0.06). On the other hand, among 441 with wild-type (wt) NPM1 and without FLT3-ITD, RI, LFS and OS were not significantly different for 155 patients with DNMT3A mutations compared to 286 patients with DNMT3Awt (2-year RI: 22% vs. 19%, HR: 1.36: p= 0.24; 2-year LFS: 62% vs. 66%, HR: 1.14, p=0.51; 2-year OS: 66% vs. 71%, HR: 1.14, p=0.53). In 125 patients with FLT3-ITD and NPM1wt, RI was significantly higher for 44 patients with DNMT3A mutations (30% vs. 18%, HR: 2.32, p=0.03), although LFS and OS were not significantly different (58% vs. 67%, HR: 1.62, p=0.12; 63% vs 70%, HR: 1.33, p=0.41, respectively).

Finally, among 711 patients with abnormal cytogenetics, 217 (31%) patients had DNMT3A mutations. MVA revealed no significant impact of DNMT3A mutations on RI, LFS or OS. Poor-risk cytogenetics were associated with worse LFS, OS and increased RI. Older age negatively affected LFS and OS.

In conclusion, we have found that triple-positive patients (DNMT3A, NPM1, and FLT3-ITD) are the most frequent, while DNMT3A co-occurrence with either FLT3 or NPM1 mutations alone is less common. The impact of DNMT3A mutations on post-transplant outcomes in AML patients in CR1 varies based on karyotype and co-mutations. DNMT3A mutations negatively affects post-transplant outcomes specifically in patients with normal karyotype and either NPM1 mutation without FLT3-ITD, or FLT3-ITD and NPM1wt. No significant impact was observed in other settings.