Invited reviewPrognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review
Introduction
Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q12) and the PML/RARα gene fusion [1]. It accounts for 10–15% of approximately 13,400 new cases of acute myeloid leukemia (AML) each year among adults in the United States [2]. The prognosis of APL has improved tremendously over the last few decades due to the application of all trans-retinoic acid (ATRA) and arsenic trioxide [1]. Further effort to improve outcomes with risk-adapted therapy has also been utilized in APL [3]. Total white blood cell (WBC) count at the time of diagnosis is mostly used for such risk-stratification approach [4].
The fms-like tyrosine kinase 3 (FLT3) gene, which encodes a class 3 receptor tyrosine kinase, plays an important role in hematopoiesis [5]. Two distinct forms of FLT3 mutations have been identified, internal tandem duplication (ITD) in the juxtamembrane domain and a point mutation within the activation loop of the tyrosine kinase domain (TKD) which mostly affects aspartate 835 (D835). Both mutations are thought to be involved in leukemogenesis by constitutively activating the receptor [6]. FLT3 ITD is found in 20–30% of patients with AML who have no cytogenetic abnormalities and has been reported to be an independent prognostic marker in these patients [7]. In APL, the prognostic relevance of FLT3 mutations is less clear. Although previous studies have explored the impact of FLT3 mutations on outcomes of APL, these studies have been limited by a relatively small number of patients [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Therefore, we conducted a systematic review to investigate the prognostic significance of FLT3 mutations for APL.
Section snippets
Selection of studies
Studies were eligible for inclusion in the meta-analysis if they met all of the following criteria. (1) published up to February 2009 as original articles written in English, (2) included only untreated APL patients, and (3) described survival information (overall survival [OS] and/or disease-free survival [DFS]) based on FLT3 status: ITD, TKD mutation, and wild type. Studies were excluded if they focused exclusively on children or on AML. Multiple reports of a single study were considered as
Study characteristics
As shown in Table 1, 11 studies with a total of 1063 subjects were included in this systematic literature review. Six studies were from Europe [9], [10], [13], [14], [15], [16] and five were from Asia [8], [11], [12], [17], [18]. The frequency of FLT3 ITD mutation varied among studies (12–38%). The frequency of FLT3 TKD mutation ranged from 2% to 20%.
FLT3 ITD mutation was associated with a higher WBC count at the time of diagnosis of APL than subjects without this mutation in most studies. Six
Discussion
While the prognostic implication of FLT3 mutation status in AML patients with normal cytogenetics is well described [7], its importance in APL remains controversial. There have been several studies [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18] investigating the prognostic significance of FLT3 mutation status in APL patients, but these studies have been limited by their relatively small sample sizes, making it difficult to detect its actual effect on outcomes. Meta-analysis is a
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