Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review

doi:10.1016/j.leukres.2010.01.001

Leukemia Research

Volume 34, Issue 7, July 2010, Pages 831-836

https://doi.org/10.1016/j.leukres.2010.01.001 Get rights and content

Abstract

The fms-like tyrosine kinase 3 (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are frequent in acute promyelocytic leukemia (APL). To evaluate their prognostic significance, we performed a systematic review and meta-analysis. Eleven studies covering a total of 1063 subjects were included in this review. Incidence of ITD and TKD mutations was 12–38% and 2–20%, respectively. In 9 of 11 studies, ITD was associated with high WBC count at the time of diagnosis, which is a known prognostic indicator in APL. Patients with ITD had inferior 3-year overall survival compared to patients without ITD (risk ratio 1.42, 95% CI: 1.04–1.95). Similarly, ITD was also associated with adverse 3-year disease-free survival (risk ratio 1.48, 95% CI: 1.02–2.15). There were only two studies that evaluated the association of TKD mutation in APL; both showed a trend towards worse survival in patients with mutated TKD. In conclusion, FLT3 ITD is associated with high WBC at diagnosis in patients with APL. Although the available literature is limited to observational studies, our systematic review suggests that FLT3 mutations, especially ITD, can adversely affect overall survival and disease-free survival in APL.

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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The objective was to determine the prevalence of FLT3/ITD and NPM1 in Chilean patients and their association with clinical data and prognosis.
Two hundred and thirty-two children were studied between 2011 and 2017, the median being 8.6 years (ranging from 1 to 18 months). Acute promyelocytic leukemia (APL) was diagnosed in 29%. The FLT3/ITD-mutated in non-promyelocytic AML was at 10% (14/133) and the FLT3/TKD, at 3.7% (2/54). In APL, it was at 25.4% (16/63). In non-promyelocytic AML, the FLT3/ITD-mutated was associated with a high leucocyte count, the median being 28.5 x mm³ (n = 14) versus 19.4 x mm³ (n = 119), (p = 0.25), in non-mutated cases. In APL, the median was 33.6 x mm3 (n = 15) versus 2.8 x mm3 (n = 47), (p < 0.001). The five-year overall survival (OS) in non-promyelocytic AML with non-mutated and mutated FLT3/ITD were 62.7% and 21.4%, respectively, (p < 0.001); the 5-year event-free survival (EFS) were 79.5% and 50%, respectively, (p < 0.01). The five-year OS in APL with non-mutated and mutated FLT3/ITD was 84.7% and 62.5%, respectively, (p = 0.05); the 5-year EFS was 84.7% and 68.8%, respectively, (p = 0.122). The NPM1 mutation was observed in 3.2% (5/155), all non-promyelocytic AML with the normal karyotype.
The FLT3/ITD mutation was observed more frequently in APL and associated with a higher white cell count at diagnosis. However, the most important finding was that the FLT3/ITD mutation was associated with a shorter survival in non-promyelocytic AML.
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The purpose of this study was to explore the outcomes of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) plus idarubicin (IDA) as a frontline treatment in adult patients with acute promyelocytic leukemia (APL).
We analyzed the outcomes of ATRA and intravenous ATO plus IDA as a frontline induction therapy in 118 patients with APL with high-risk (HR) and standard-risk (SR) disease from January 2008 to December 2017. The medical records of 118 patients with APL (HR, n = 45; SR, n = 73) who received the frontline triple combination regimen at Henan Provincial People’s Hospital and Tongji Hospital were retrospectively reviewed. Consolidation therapy comprised 6 cycles of ATO and ATRA plus IDA, and IDA was administered in 1 to 4 cycles of consolidation therapy based on the comparable clinical efficacy compared with 6 cycles and fewer side effects to myocardium without subsequent maintenance therapy.
Of 118 patients, there were 3 (2.5%) early deaths and 115 (97.5%) hematologic complete remissions; 102 (88.7%) of 115 patients achieved molecular complete remission following induction therapy, and all patients were polymerase chain reaction-negative for promyelocytic leukemia-retinoic acid receptor alpha after the first cycle of consolidation therapy. The 5-year overall survival (OS) and event-free survival (EFS) were 93.0% ± 2.9% and 92.4% ± 3.0%, respectively. Early death, hematologic complete remissions, molecular complete remissions, and toxicities were comparable between the HR and SR groups. The cumulative incidence of relapse in the HR group was 4.7% (n = 2), and the cumulative incidence of relapse in the SR group was 0. The OS and EFS of the SR and HR groups were comparable (92.3% ± 4.5% vs. 92.8% ± 4.0%; X² = 0.263; P = .608; 92.3% ± 4.5% vs. 91.1% ± 4.2%, X² = 0.917; P = .338). The total dosage of IDA was approximately 181 to 258 mg, and no patient experienced cardiotoxicity. OS and EFS were not influenced by fms-related tyrosine kinase 3 internal tandem duplication mutation status (P = .405 and P = .528, respectively).
The triple combination of ATRA and ATO plus IDA as both an induction and consolidation therapy for the HR and SR groups attained excellent outcomes, and this regimen was effective, safe, and easy, without maintenance therapy. The triple combination treatment might be a preferred frontline therapy for patients with APL, especially for those with HR or the APL fms-related tyrosine kinase 3 internal tandem duplication mutation.
FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias
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Citation Excerpt :
Recently, the frontline combination of ATRA and arsenic in non–high-risk APL allowed the cure of most patients without the need for DNA-damaging chemotherapy.44-48 Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 gene (FLT3) occurs with a much higher frequency in APL (35%-40%) than in other AMLs (20%-25%).49-56 FLT3 activation is tightly associated with a high white blood cell count at presentation, cases designated as high-risk APL.
Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3-internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for this effect remain unknown. Using mouse APL models, we unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response. Remarkably, although the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is blunted, as is PML nuclear body reformation and activation of P53 signaling. Critically, the combination of ATRA and arsenic fully rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL eradication. Moreover, arsenic targeting of normal PML also contributes to APL response in vivo. These unexpected results explain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination.
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Invited reviewPrognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review

Abstract

Introduction

Section snippets

Selection of studies

Study characteristics

Discussion

Blood

Blood

Blood

Blood

Control Clin Trials

Cancer statistics, 2007

CA Cancer J Clin

Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group

J Clin Oncol

FLT3 in human hematologic malignancies

Leuk Lymphoma

Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis

Leukemia

Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia

Leukemia

Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16)

Hematol J

Invited review
Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review