Impact of <i>FLT3</i>-ITD length on prognosis of acute myeloid leukemia

Liu, Song‐Bai; Dong, Haojie; Bao, Xiebing; Qiu, Qiao‐Cheng; Li, Hongzhi; Shen, Hongjie; Ding, Zixuan; Wang, Chao; Chu, Xiaoling; Yu, Jing-Qiu; Tao, Tao; Zheng, Li; Tang, Xiaowen; Chen, Suning; Wu, Depei; Li, Ling; Xue, Sheng‐Li

doi:10.3324/haematol.2018.191809

Cited by 58 publications

(59 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Other reports did not show a significant impact of FLT3-ITD insertion length on AML outcomes 10 . Theoretically, longer FLT3-ITD has stronger phosphorylation signals and higher constitutive proliferative capacity regardless of the insertion site, reflected by less sensitivity to TKI when AML cell lines were exposed to quizartinib 28 , but this does not seem to be corroborated in the clinical experience, as shown in our analysis.…”

Section: Discussioncontrasting

confidence: 62%

“…The impact of FLT3-ITD length on the prognosis of patients with FLT3 mutant AML is still controversial [10][11][12]28 . Liu et al reported worse outcomes with longer FLT3-ITD with 3-year OS of 27% compared with 61% for short FLT3-ITD (p = 0.004) 28 . Other reports did not show a significant impact of FLT3-ITD insertion length on AML outcomes 10 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia

et al. 2020

View full text Add to dashboard Cite

FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24-0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7-1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25-0.66, p < 0.001), single ITD mutation (HR = 0.55, 95% CI: 0.34-0.88, p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35-0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19-0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.

show abstract

Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Taken together, the interpretation of the data on allelic ratio remains controversial in this setting, and further studies are needed to better elucidate the prognostic impact of allelic burden so that treatment decisions based on it may be optimized. Other FLT3 -ITD-related variables that may have prognostic significance in this setting are the base pair size of the FLT3 -ITD mutation and its insertion site; e.g., increasing FLT3 -ITD size has been shown to be associated with decreasing OS and RFS [42–44].…”

Section: Prognostic Impact Of Flt3 Mutations In Newly Diagnosed Amlmentioning

confidence: 99%

Targeting FLT3 mutations in AML: review of current knowledge and evidence

et al. 2019

View full text Add to dashboard Cite

Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7–10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient’s disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.

show abstract

“…Two additional prognostic indicators in FLT3-ITD- positive AML cases established in the last few years are the mutational burden in each patient defined as the ratio between mutant and wild-type FLT3-ITD alleles (allelic ratio, AR) [12, 17, 18] and the co-occurrence of FLT3-ITD with a cytogenetically cryptic translocation of chromosomes 5 and 11 or t(5;11)(q35;p15) [19]. This translocation leads to fusion of the nucleoporin ( NUP98 ) gene on chromosome 11 and the gene for nuclear receptor binding SET-domain protein 1 ( NSD1 ) of chromosome 5 ( NUP98-NSD1 ).…”

Section: Introductionmentioning

confidence: 99%

MutatedWT1,FLT3-ITD,andNUP98-NSD1Fusion in Various Combinations Define a Poor Prognostic Group in Pediatric Acute Myeloid Leukemia

Niktoreh

Walter

Zimmermann

et al. 2019

Journal of Oncology

View full text Add to dashboard Cite

Acute myeloid leukemia is a life-threatening malignancy in children and adolescents treated predominantly by risk-adapted intensive chemotherapy that is partly supported by allogeneic stem cell transplantation. Mutations in theWT1gene andNUP98-NSD1fusion are predictors of poor survival outcome/prognosis that frequently occur in combination with internal tandem duplications of the juxta-membrane domain ofFLT3(FLT3-ITD).To re-evaluate the effect of these factors in contemporary protocols, 353 patients (<18 years) treated in Germany with AML-BFM treatment protocols between 2004 and 2017 were included. Presence of mutatedWT1andFLT3-ITDin blasts (n=19) resulted in low 3-year event-free survival of 29% and overall survival of 33% compared to rates of 45-63% and 67-87% in patients with only one (onlyFLT3-ITD; n=33,onlyWT1mutation; n=29) or none of these mutations (n=272). IncludingNUP98-NSD1and high allelic ratio (AR) ofFLT3-ITD(AR ≥0.4) in the analysis revealed very poor outcomes for patients with co-occurrence of all three factors or any of double combinations. All these patients (n=15) experienced events and the probability of overall survival was low (27%). We conclude that co-occurrence ofWT1mutation,NUP98-NSD1,andFLT3-ITDwith an AR ≥0.4 as triple or double mutations still predicts dismal response to contemporary first- and second-line treatment for pediatric acute myeloid leukemia.

show abstract

Impact of FLT3-ITD length on prognosis of acute myeloid leukemia

Cited by 58 publications

References 20 publications

Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia

Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia

Targeting FLT3 mutations in AML: review of current knowledge and evidence

MutatedWT1,FLT3-ITD,andNUP98-NSD1Fusion in Various Combinations Define a Poor Prognostic Group in Pediatric Acute Myeloid Leukemia

Contact Info

Product

Resources

About