Prognostic Impact of FLT3-ITD and DNMT3A R882 Double Mutations in Patients with Acute Myeloid Leukemia

Background: FLT3-ITD and DNMT3A R882 mutations are both independent factors for poor prognosis of acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been confirmed to improve the outcome of AML with either of gene mutations. However, the clinical characteristics of AML with both of FLT3-ITD and DNMT3A R882 mutations and their outcome post allo-HSCT had been rarely evaluated.

Objective: To investigate the clinical characteristics and transplantation outcomes of AML patients with the double mutations.

Methods: A total of 241 patients were included in this retrospective analysis. Molecular genetic mutation sets in bone marrow (including FLT3-ITD, DNMT3A, C-kit, CEBPA, FLT3-TKD, and NMP1) of 241 AML patients were detected at diagnosis using direct sequencing method. And the clinical data of these patients were analyzed retrospectively.

Results: (1)According to the genetic mutation types, the 241 AML patients were divided into four groups: FLT3-ITD+DNMT3A R882+, FLT3-ITD+DNMT3A R882-, FLT3-ITD-DNMT3A R882+ and FLT3-ITD-DNMT3A R882- groups, which consisted of 19, 38, 21 and 163 patients, respectively. (2) Patients with FLT3-ITD+DNMT3A R882+ have high white blood cell count and a low complete remission rate after first induction chemotherapy (52.6%), which are common in M5、M2、M4 with normal chromosome karyotype, higher early cumulative incidence of relapse(6m-CIR 36.8±1.3%、12m-CIR 49.7±1.6%) and cumulative mortality rate (6m-CMR 26.3±10.1%、12m-CMR 48.5±11.8%) . (3) 2-year CIR of the FLT3-ITD+DNMT3A R882+ was (72.2±2.7%), which was significantly higher than that of the FLT3-ITD+DNMT3A R882- group (38.6±0.7%) and FLT3-ITD-DNMT3A R882+ group (36.8±1.6%). While the 2-year overall survival (OS) rate and 2-year leukemia-free survival (LFS) rate of double mutation group were (30.9±13.3% ) and (11.3±10.2%), respectively, which were considerably lower than those of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups (2y-OS: 67.5±7.8%, 61.4±12.4%: 2y-LFS: 47.9±8.4%, 56.8±12.5%). Meanwhile, the 2-year CIR rates of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups were significantly higher than that of the FLT3-ITD-DNMT3A R882- group (16.3±0.1%), while their 2-year OS rate and 2-year LFS rate were significantly lower than those of the FLT3-ITD-DNMT3A R882- group (2y-OS: 82.5±3.1%、2y-LFS: 80.9±3.2%). (3) Univariate and multivariate analyses revealed that disease status prior to transplantation, grade III-IV aGVHD, FLT3-ITD, DNMT3A R882 and FLT3-ITD+DNMT3A R882+ were independent factors for poor prognosis post transplantation.

Conclusion: AML patients with FLT3-ITD and DNMT3A R882 double mutations still present a very poor prognosis after transplantation with low OS and LFSas well as a high CIR rate. Therefore, it is necessary to explore prevention strategy for relapse post transplantation.