Dataset Information

Profiling of somatic mutations and fusion genes in acute myeloid leukemia patients with FLT3-ITD or FLT3-TKD mutation at diagnosis reveals distinct evolutionary patterns.

ABSTRACT:

Background

The receptor tyrosine kinase FLT3 with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) is a poor prognostic factor; however, the prognostic significance of missense mutation in the tyrosine kinase domain (FLT3-TKD) is controversial. Furthermore, the accompanying mutations and fusion genes with FLT3 mutations are unclear in acute myeloid leukemia (AML).

Methods

We investigated FLT3 mutations and their correlation with other gene mutations and gene fusions through two RNA-seq based next-generation sequencing (NGS) method and prognostic impact in 207 de novo AML patients.

Results

FLT3-ITD mutations were positive in 58 patients (28%), and FLT3-TKD mutations were positive in 20 patients (9.7%). FLT3-ITD was associated with a higher white blood cell count (WBC, mean 72.9 × 10⁹/L vs. 24.2 × 10⁹/L, P = 0.000), higher bone marrow blasts (mean 65.9% vs. 56.0%, P = 0.024), and NK-AML (normal karyotype) (64.8% vs. 48.4%, P = 0.043). NPM1 and DNMT3A mutations were enriched in FLT3-ITD (53.5% vs. 15.3%, P = 0.000; 34.6% vs. 13%, P = 0.003). However, the mutations of CEBPA were excluded in FLT3-AML (3.8% vs. 0% vs. 19.8%, P = 0.005). Mutations of Ras and TP53 were unlikely associated with FLT3-ITD (1.9% vs. 20.6%, P = 0.006; 0% vs. 6.1%, P = 0.04). The common fusion genes (> 10%) in FLT3-ITD had MLL-rearrangement and NUP98-rearrangement, while the common fusion genes in FLT3-TKD had AML1-ETO and MLL-rearrangement. Two novel fusion genes PRDM16-SKI and EFAN2-ZNF238 were identified in FLT3-ITD patients. Gene fusions and NPM1 mutation were mutually excluded in FLT3-ITD and FLT3-TKD patients. Their patterns of mutual exclusivity and cooperation among mutated genes suggest that additional driver genetic alterations are required and reveal two evolutionary patterns of FLT3 pathogenesis. Patients with FLT3-ITD had a lower CR (complete remission) rate, lower 3-year OS (overall survival), DFS (disease-free survival), and EFS (event-free survival) compared to FLT3_wtAML. NK-AML with FLT3-ITD had a lower 3-year OS, DFS, and EFS than those without, while FLT3-TKD did not influence the survival in whole cohort and NK-AML. Besides, we found that FLT3-ITD/TET2 bimutation defined a poor prognostic subgroup.

Conclusions

Our study offers deep insights into the molecular pathogenesis and biology of AML with FLT3-ITD and FLT3-TKD by providing the profiles of concurrent molecular alterations and the clinical impact of FLT3-ITD and FLT3-TKD on AML patients.

SUBMITTER: Guan W

PROVIDER: S-EPMC8033687 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.