Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia

Abstract

FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in hematological malignancies. FLT3 internal tandem duplication (FLT3-ITD) mutations located in juxtamembrane domain (JMD) and tyrosine kinase domain 1 (TKD1) regions account for two-thirds of all FLT3 mutations. The outcome of patients remains unsatisfactory, with low survival rates. It is not yet known whether the different mutations within the FLT3 gene are all associated with patient outcome. In addition, the cause of FLT3-ITD in-frame duplication events remains unknown. Although there are some published studies investigating the FLT3-ITD mutation and its clinical implications in Chinese acute myeloid leukemia (AML) patients, sample sizes tend to be small and detailed molecular profiles of FLT3 mutations are lacking in these studies. In our study, 227 FLT3-ITD sequences were analyzed from 227 Chinese de novo AML patients. ITD were next classified into 3 types based on molecular profiles of insertion DNA sequences: DNA complete duplication (type I), DNA partial duplication (type II) and complete random sequence (type III). From the 154 patients, we confirmed that high ITD allelic ratio (≥.5) and allogeneic stem cell transplant treatment under CR1 are independent prognostic factors. We also presented evidence that ITD integration sites in the hinge region or beta1-sheet region are an unfavorable prognostic factor in adult AML patients with FLT3-ITD mutations. These findings may help to decipher the mechanisms of FLT3-ITD in-frame duplication events and stratify patients when considering different therapeutic combinations.

Keywords: FLT3-ITD; acute myeloid leukemia; insertion sites; kinase activity; prognostic value.

Figure 1

Molecular characteristics and classification of FLT3‐ITD. All 227 ITD insertion base sequences were divided into 3 types or 5 subtypes based on their molecular profiles. Based on the functional regions from Griffith and Kayser, ITD were categorized into 8 subgroups. The black color regions stand for duplicated amino acid sequences, the blue color regions stand for random amino acid sequences or amino acids translated by transcripted partial intron sequences. ITD, internal tandem duplication

Figure 2

Survival analysis for FLT3‐ITD‐mutated acute myeloid leukemia (AML) according to mutant/wt ratio. A, Estimated 3 y overall survival (OS) rate for patients with mutant/wt ratio >.5 vs <.5; the group differences were examined using a log‐rank test. B, Estimated 3 y disease‐free survival (DFS) rate for patients with mutant/wt ratio >.5 vs <.5; the group differences were examined using a log‐rank test

Figure 3

Survival analysis for FLT3‐ITD‐mutated acute myeloid leukemia (AML) according to insertion sites. A, Estimated 3 y overall survival (OS) rate for FLT3‐ITD insertion sites within JMD vs TKD1 region; the group differences were examined using a log‐rank test. B, Estimated 3 y disease‐free survival (DFS) rate for FLT3‐ITD insertion sites within JMD vs TKD1 region; group differences were examined using a log‐rank test. C, Estimated 6 month and 6 month‐3 y DFS rate for FLT3‐ITD insertion sites within JMD vs TKD1 region; the group differences were examined by landmark analysis. D, Estimated 3 y OS rate for FLT3‐ITD insertion sites within the beta1‐sheet or hinge region vs all other insertion sites; the group differences were examined using a log‐rank test. E, Estimated 3 y DFS rate for FLT3‐ITD insertion sites within the beta1‐sheet or hinge region vs all other insertion sites; the group differences were examined using a log‐rank test. F, Estimated 6 month and 6 month‐3 y DFS rate for FLT3‐ITD insertion sites within the beta1‐sheet or hinge region vs all other insertion sites, the group differences were examined by landmark analysis. ITD, internal tandem duplication

Figure 4

Efficacy of allogeneic stem cell transplant (Allo‐SCT) for FLT3‐ITD‐Hmutated acute myeloid leukemia (AML) patients. A, Overall survival (OS) rate for patients received Allo‐SCT under first complete remission (CR1) and others. The group differences were examined using a log‐rank test. B, Disease‐free survival (DFS) rate for received Allo‐SCT under CR1 and others. The group differences were examined using a log‐rank test. ITD, internal tandem duplication

Figure 5

Efficacy of NPM1 mutation on FLT3‐ITD‐mutated acute myeloid leukemia (AML). A, Overall survival (OS) rate for patients in low‐risk subgroup (NPM1 ^MUT with FLT3‐ITD low AR), medium risk subgroup (NPM1 ^WT with FLT3‐ITD low AR, or NPM1 ^MUT with FLT3‐ITD high AR), and high‐risk subgroup (NPM1 ^WT with FLT3‐ITD high AR). The group differences were examined using a log‐rank test. B, Disease‐free survival (DFS) rate for patients in low risk subgroup (NPM1 ^MUT with FLT3‐ITD low AR), medium risk subgroup (NPM1 ^WT with FLT3‐ITD low AR, or NPM1 ^MUT with FLT3‐ITD high AR), and high risk subgroup (NPM1 ^WT with FLT3‐ITD high AR). The group differences were examined using a log‐rank test. C, OS rate for NPM1‐mutated patients who achieved allogeneic stem cell transplant (Allo‐SCT) under CR1 and others. The group differences were examined using a log‐rank test. D, DFS rate for NPM1‐mutated patients who achieved Allo‐SCT under CR1 and others. The group differences were examined using a log‐rank test. E, OS rate for NPM1 ^WT patients who achieved Allo‐SCT under CR1 and others. The group differences were examined using a log‐rank test. F, DFS rate for NPM1 ^WT patients who achieved Allo‐SCT under CR1 and others. The group differences were examined using a log‐rank test. ITD, internal tandem duplication