Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

Tao, Shandong; Chen, Yue; Deng, Yuan; Song, Lixiao; Shi, Yuyue; Ling, Lanlan; Ding, Banghe; He, Zhengmei; Yu, Liang

doi:10.3892/ol.2019.11051

Cited by 19 publications

(21 citation statements)

References 32 publications

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“…In our study, 50% of patients had a normal karyotype by conventional cytogenetic analysis at diagnosis. Consistent with other studies, there were no significant differences in the OS or EFS for normal or abnormal karyotypes in patients with FLT3-ITD mutations ( P =0.699) [ 8 , 19 ]. FLT3-ITD mutations coexisting with other specific molecular genetics and cytogenetic alterations have been frequently reported [ 8 ].…”

Section: Discussionsupporting

confidence: 89%

“…In vitro studies have reported that FLT3 inhibitors work synergistically with chemotherapy to induce cytotoxicity [ 22 , 23 ]. Selective next generation FLT3 therapies (gliteritinib, crenolanib, quizartinib) have greater specificity for FLT3 and higher potency than multitargeted TKIs (midostaurin and sorafenib), and clinical trials have shown an improvement in OS even in relapsed/refractory patients [ 2 , 19 ]. This is promising because relapse is common in these patients, and relapsed patients usually present with higher FLT3-ITD mutation burdens and have a poorer response to treatment [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Median age at diagnosis 13 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Gender WBC count of >100×10 9 /L at diagnosis; b) enocitabine, idarubicin, intrathecal cytarabine; c) cytarabine, idarubicin, mitoxantrone. Abbreviations: AML, acute myeloid leukemia; CR, complete remission; DOD, died of disease; FAB, French-American-British classification; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor; N, number; TRM, treatment-related mortality.…”

Section: N 18mentioning

confidence: 99%

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Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

et al. 2020

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Background: Acute myeloid leukemia (AML) with internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with poor outcomes. This study aimed to analyze the outcomes of pediatric AML patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era. Methods: We retrospectively reviewed and identified 18 patients diagnosed with non-M3 AML with FLT3-ITD mutations at Seoul National University Children's Hospital between May 2008 and August 2019. Results: The median age was 13 years (range, 6-19 yr). The median follow-up time was 43 months (range, 6-157 mo). Fourteen patients received BH-AC-based (N4-Behenoy1-1-β-D-arabinofuranosy1cytosine) and 4 received cytarabine-based induction chemotherapy. Complete remission (CR) was achieved in 72.2% of the patients after the first induction chemotherapy and 80% of the patients achieved CR after salvage therapy. The overall CR rate was 94% (17/18 patients). These 17 patients underwent hematopoietic stem cell transplantation (9 matched unrelated donors, 5 matched related donors, and 3 haploidentical donors). Relapse occurred in 22% of the patients. Event free survival and overall survival rates were 53.8±12.1% and 53.6±12.1%, respectively, and they were not significantly different according to the type of induction chemotherapy (P=0.690) or the type of donor (P=0.102). Conclusion: This study outlines the outcomes of pediatric AML patients with FLT3-ITD-mutations in one institution over a decade. Outcomes were significantly improved in this study compared to our previous report in 2004, where RFS and EFS were 0%. This study can provide baseline data for pediatric patients in the pre-FLT3 inhibitor era.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: N 18mentioning

confidence: 99%

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Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

et al. 2020

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“…FMS-like tyrosine kinase 3 (FLT3) mutation is one of the most common genetic abnormalities in AML patients [7]. Survival analyses indicated that FLT3 mutation was significantly associated with poor OS, RFS and EFS using data provided by Bullinger L et al [14], which was consisted with previous studies [39,40]. Therefore, further investigation is important for better understanding the biological roles of FLT3 mutations in AML.…”

Section: Discussionmentioning

confidence: 88%

Identification of the key genes and microRNAs in adult acute myeloid leukemia with FLT3 mutation by bioinformatics analysis

Chen¹,

Chen²,

Zhu³

et al. 2020

Int. J. Med. Sci.

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Background: Associated with poor prognosis, FMS-like tyrosine kinase 3 (FLT3) mutation appeared frequently in acute myeloid leukemia (AML). Herein, we aimed to identify the key genes and miRNAs involved in adult AML with FLT3 mutation and find possible therapeutic targets for improving treatment. Materials: Gene and miRNA expression data and survival profiles were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. EdgeR of R platform was applied to identify the differentially expressed genes and miRNAs (DEGs, DE-miRNAs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction network, miRNA-mRNA regulatory network and clustering modules analyses were performed by STRING database and Cytoscape software. Results: Survival analysis showed FLT3 mutation led to adverse outcome in AML. 24 DE-miRNAs (6 upregulated, 18 downregulated) and 250 DEGs (54 upregulated, 196 downregulated) were identified. Five miRNAs had prognostic value and the results matched their expression levels (miR-1-3p, miR-10a-3p, miR-10a-5p, miR-133a-3p and miR-99b-5p). GO analysis showed DEGs were enriched in skeletal system development, blood vessel development, cartilage development, tissue morphogenesis, cartilage morphogenesis, cell morphogenesis involved in differentiation, response to growth factor, cell-substrate adhesion and so on. The KEGG analysis showed DEGs were enriched in PI3K-Akt signaling pathway, ECM-receptor interaction and focal adhesion. Seven genes (LAMC1, COL3A1, APOB, COL1A2, APP, SPP1 and FSTL1) were simultaneously identified by hub gene analysis and module analysis. SLC14A1, ARHGAP5 and PIK3CA, the target genes of miR-10a-3p, resulted in poor prognosis. Conclusion: Our study successfully identified molecular markers, processes and pathways affected by FLT3 mutation in AML. Furthermore, miR-10a-3p, a novel oncogene, might involve in the development of FLT3 mutation adult AML by targeting SLC14A1, ARHGAP5 and PIK3CA.

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“…The relationship between clinical relevance and the FLT3 mutation status of human AML has been discussed in several studies [ 19 , 23 , 39 ]. From a clinical perspective, AML patients with FLT3-ITD mutations have been associated with poor prognoses, increased white blood cell count at diagnosis, and an increased risk of relapse [ 25 , 41 ]. Moreover, WBC count is also the most important prognostic factor in acute promyelocytic leukemia (APL), and there are poorer outcomes for patients presenting with high WBC counts [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Activating Mutation in the Receptor Tyrosine Kinase FLT3 with Clinicopathological Relevance in Canine Mast Cell Tumors

Manachai

Rattanapinyopituk

Fonghem

et al. 2022

Veterinary Medicine International

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Recent research has focused on the receptor tyrosine kinase (RTK) KIT which is involved in the pathogenesis of canine mast cell tumors (MCT). However, the role of other RTKs in this neoplasm remains unclear. The present study aimed to determine the frequency of FLT3 mutations and to evaluate the mutational status and clinicopathological relevance of canine MCT patients. There were a total of 20 cases that were cytologically and histopathological diagnosed as canine MCTs; genomic polymerase chain reaction (PCR) and Sanger sequencing were used to identify mutations. For the juxtamembrane (JM) domain, the FLT3 14/15 primer pair was used to investigate exon 14/15 loci. Based on genomic PCR amplification of exon 14/15 and 20 of the FLT3 gene and Sanger sequencing of 20 cases of canine MCTs, the overall frequency of FLT3 mutation in canine MCTs was 75%. The majority of FLT3 mutations (70%) were internal tandem duplications (ITD) of the JM domain, while one case arose from deletion mutations of the tyrosine kinase domain (TKD). However, double mutations were not observed in this study. Furthermore, there is also clinicopathological relevance to MCT dogs carrying FLT3-ITD mutations, showing a tendency toward leukocytosis due to neutrophilia, and resembling human acute myeloid leukemia (AML) with FLT3-ITD mutations. A subset of MCTs with FLT3-ITD mutations, showing an enhanced signal of phosphorylated ERK1/2 identified by immunoblotting, suggests that an activating mutation may be driven by a distinct signal of the ERK pathway. Our results indicate that FLT3-ITD mutation is an oncogenic driver of canine MCTs, and that it shares some clinicopathologic features with human AML. These findings may offer new opportunities for further studies on canine mast cell tumorigenesis and a novel therapeutic target for canine MCT cases harboring FLT3-ITD mutations.

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Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

Cited by 19 publications

References 32 publications

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

Identification of the key genes and microRNAs in adult acute myeloid leukemia with FLT3 mutation by bioinformatics analysis

Activating Mutation in the Receptor Tyrosine Kinase FLT3 with Clinicopathological Relevance in Canine Mast Cell Tumors

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