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.

<p>Acute myeloid leukemia patient with <em>FLT3-ITD</em> and <em>NPM1</em> double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis </p>

“…large group of AML patients, 18 low FLT3-ITD AR with NPM1 mutated AML, which was classified in NCCN as favorable risk level, should be considered as intermediaterisk group. And the similar conclusion was also reported by Liu et al 19 . Besides, some studies indicated that allo-HSCT improves the prognosis in NPM1 mutated AML with FLT3-ITD low AR.…”

“…Besides, some studies indicated that allo-HSCT improves the prognosis in NPM1 mutated AML with FLT3-ITD low AR. [19][20][21] Moreover, Patel et al 23 reported that high variant allele frequency of NPM1 predict poor outcomes in de novo AML, even after undergoing hematopoietic stem cell transplantation. And the effect of high NPM1 variant allele frequency on prognosis was not affected by the level of FLT-ITD AR.…”

“…However, this risk classification on FLT3-ITD and NPM1 double mutated AML was not accepted by some clinicians, and several studies provided evidence that this type of AML is with unfavorable risks. [16][17][18][19][20][21] What is the optimal treatment for AML FLT3-ITD+/NPM1+ patients is also under investigation. In this study, we retrospectively analyzed the clinical features and risk factors of AML FLT3-ITD+/NPM1+ , and discussed whether hematopoietic stem cell transplantation is necessary after complete remission (CR).…”

Prognostication refinement in NPM1‐mutated acute myeloid leukemia stratified by FLT3‐ITD status with different induction doses of cytarabine

“… 5 , 6 Approximately 40% of NPM1 mut cases are concurrent with FLT3 ‐ITD, which impairs the favorable effect of NPM1 mut . 20 , 21 , 22 , 23 , 24 Despite the increasing use of FLT3 inhibitors, the mainstay of the “7 + 3” regimen in treatment of FLT3 ‐ITD (+) AML is still unshakable. In developing countries, FLT3 inhibitors cannot typically be prescribed as conventional drugs due to their lack of accessibility, economic burden, and tolerance by some patients.…”

“…Other studies also demonstrated no significant prognostic difference between patients with NPM1 mut / FLT3 ‐ITD low and NPM1 mut / FLT3 ‐ITD high . 21 , 22 , 23 , 24 Thus, it appeared reasonable to re‐allocate NPM1 mut / FLT3 ‐ITD low to an intermediate‐risk. This is embodied in the very latest published recommendations, 2022 European LeukemiaNet risk classification by genetics at initial diagnosis in AML, which categorizes NPM1 mut / FLT3 ‐ITD as intermediate‐risk irrespective of FLT3 ‐ITD AR.…”