scholarly journals Targeting the FLT3 Mutation in Acute Myeloid Leukaemia

2017 ◽  
Vol 13 (02) ◽  
pp. 139 ◽  
Author(s):  
Sabine Kayser ◽  
Richard F Schlenk ◽  
◽  
◽  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Acute Myeloid

Acute myeloid leukaemia (AML) exhibiting an internal tandem duplication of the FLT3 gene (FLT3-ITD) is an aggressive haematologic malignancy with a poor prognosis due to a high relapse rate and very limited options after relapse with conventional salvage regimens, whereas the prognostic impact of point mutations in the tyrosine kinase domain of the FLT3 gene (FLT3-TKD) are less clear. A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by the FLT3 mutation, thus interrupting signalling pathways. Early clinical trials of these agents as monotherapy failed to elicit enduring complete responses, leading to clinical testing of FLT3 TKI in combination with conventional chemotherapy. Midostaurin has demonstrated improved survival in combination with standard intensive chemotherapy as compared to standard chemotherapy alone in younger adult patients with newly diagnosed FLT3-mutated AML and is the first and currently the only approved FLT3 TKI. Newer, more selective compounds, such as gilteritinib and crenolanib, have also demonstrated significant potency and specificity. Several combination trials are ongoing or planned in both relapsed and newly diagnosed AML patients with activating FLT3 mutations.

scholarly journals Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Samantha Bruno ◽  
Lorenza Bandini ◽  
Agnese Patuelli ◽  
Valentina Robustelli ◽  
Claudia Venturi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Novel Mutation ◽  
Point Mutations ◽  
Tyrosine Kinase Domain ◽  
Driver Genes ◽  
Acute Myeloid

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin.

scholarly journals The Clinical Features and Prognosis of NPM1/FLT3-ITD/DNMT3A Triple-mutated Acute Myeloid Leukaemia

2021 ◽  
Author(s):  
Xingchun Luo ◽  
Bei Liu ◽  
Haiping Liang ◽  
Long Zhao ◽  
Yuancheng Guo ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Bioinformatics Analysis ◽  
De Novo ◽  
Prognostic Significance ◽  
Gene Expression Omnibus ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Purpose: Previous studies have shown that patients with NPM1+/FLT3-ITD+ acute myeloid leukaemia (AML) have a poor prognosis, especially those with a high FLT3-ITD allelic ratio. However, no studies have confirmed a clear prognostic impact of DNMT3A on NPM1+/FLT3-ITD+ AML patients. Methods: Our study included a total of 165 patients with newly diagnosed non-acute promyelocytic leukaemia (non-APL) AML at The First Hospital of Lanzhou University between January 2018 and June 2021. Further bioinformatics analysis was performed using the Gene Expression Omnibus (GEO) database. Results: We retrospectively studied 165 patients newly diagnosed non-APL AML and identified 11 (6.7%) patients with NPM1/FLT3-ITD/DNMT3A triple mutations. The patients with triple-mutated AML had advanced age, higher white blood cell (WBC) counts, de novo AML, normal karyotypes, and poor survival, and all were in the M4/M5 French-American-British (FAB) category. Notably, half of the patients with triple-mutated AML had mature monocyte characteristics that were difficult to distinguish from chronic myelomonocytic leukaemia (CMML). We validated the prognosis of patients with triple-mutated AML by further bioinformatics analysis and found that the GNG4 gene, one of the hub genes, was related to triple-mutated AML patients' survival. Conclusion: Our data demonstrate that DNMT3A gene mutation has adverse prognostic significance in NPM1+FLT3-ITD+comutation AML patients.

scholarly journals FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

2020 ◽  
Vol 20 (7) ◽  
pp. 513-531 ◽  
Author(s):  
Francesca L. Hogan ◽  
Victoria Williams ◽  
Steven Knapper
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Development ◽  
Clinical Prognosis ◽  
Acquired Drug Resistance ◽  
Acute Myeloid

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors have progressed through clinical development over the last 10-15 years. The last two years have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents, quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment. In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance, and the future outlook for this group of agents, including current and planned clinical trials, is discussed.

Bcr-Abl Tyrosine Kinase Domain Mutations Both Pre-Exist and Develop during Imatinib Treatment and Are Responsible for Resistance in Patients with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 639-639 ◽  
Author(s):  
Heike Pfeifer ◽  
Barbara Wassmann ◽  
Anna Pavlova ◽  
Lydia Wunderle ◽  
Patrick Brueck ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
De Novo ◽  
Point Mutations ◽  
Kinase Domain ◽  
Disease Stage ◽  
Tyrosine Kinase Domain ◽  
Imatinib Treatment ◽  
Newly Diagnosed ◽  
Imatinib Resistance ◽  
Prior Chemotherapy

Abstract Background: Point mutations in the tyrosine kinase domain (TKD) of BCR-ABL are an important cause of resistance to imatinib (IM) in pts. with CML and Ph+ ALL. The significantly inferior response to IM in Ph+ALL pts. who failed prior chemotherapy compared to those with de novo Ph+ALL suggests that treatment with cytotoxic drugs may promote the development of TKD mutations. However, it is not known whether the frequency and pattern of TKD mutations at the time of treatment initiation with TK inhibitors are related to disease stage or prior anti-leukemic therapy. Moreover, the potential of combined treatment with IM and multi-agent chemotherapy to influence the development of mutational resistance, as compared to IM alone, has not been determined. Patients and methods: 51 pts. with newly diagnosed Ph+ALL (>55 yrs.) enrolled in a GMALL study of combined IM and chemotherapy, and 68 Ph+ALL pts. who had failed prior chemotherapy and received single-agent IM as salvage therapy were analysed for the occurrence of point mutations within the TKD. Bone marrow samples collected pre-treatment, during therapy and at relapse were examined by denaturing high-performance liquid chromatography (D-HPLC) and cDNA sequencing. Results: The frequency of TKD mutations pre-IM was 44% in newly diagnosed Ph+ALL and 53% (34/64) in pts. with advanced Ph+ALL. At relapse after combination therapy (n=19), the frequency of de novo ALL pts. harbouring a TKD mutation had increased to 89% (P-loop 47%, T315I 29%, A-loop 24%), 2 pts. (11%) showed wild-type BCR-ABL. The frequency of TKD mutations in pts. with advanced disease who relapsed after IM was 55% (P-loop 73%, T315I 23%, A-loop 4 %). In both patient groups, the D-HPLC pattern showed concordance between the mutation detected in pre-therapeutic specimens and the dominant mutation detected at relapse. The CR rate in de novo pts. receiving IM induction was 90 % irrespective of detectable mutations pre-study. Bcr-abl transcripts became undetectable during the course of therapy in 40% of pts. with and 37% of pts. without a mutation. Median remission duration in pts. with a T315I mutation (n=4) was 130 d (range: 53–319d), in contrast to 526 d (range: 504–549d) with activation loop and 411 d (range: 106–745d) with P-loop mutations. To date, 7 pts. with an initially detected mutation remain in CR after median FU of 12.8 mo (range 2.4–24.5 mo.). Conclusions: Bcr-abl TKD mutations are detectable prior to first imatinib exposure in approximately 50% of Ph+ALL patients. Clinical imatinib resistance is in most cases associated with the identical mutation detected pre-IM, which is not eradicated by the combination of chemotherapy and IM. Identification and elimination of TKD mutations during early stages of treatment is essential to improve treatment.

FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1262-1270 ◽  
Author(s):  
Adam J. Mead ◽  
David C. Linch ◽  
Robert K. Hills ◽  
Keith Wheatley ◽  
Alan K. Burnett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
White Cell Count ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
The Difference ◽  
High Level ◽  
Acute Myeloid

Abstract The prognostic impact of tyrosine kinase domain (TKD) mutations of the fms-like tyrosine kinase-3 (FLT3) gene in acute myeloid leukemia (AML) is currently uncertain. To resolve this issue we screened 1107 young adult nonacute promyelocytic leukemia AML patients with known FLT3 internal tandem duplication (ITD) status for FLT3/TKDs; they were detected in 127 (11%) cases. Mutations were associated with a high white cell count (P =.006) and patients with inv(16) (P = .005) but were infrequent in patients with adverse cytogenetics and secondary AML. Overall survival (OS) at 5 years was 53% and 37% for FLT3/TKD mutant and wild-type patients respectively (odds ratio, 0.72; 95% confidence interval, 0.58 to 0.89; P = .002). For both the cumulative incidence of relapse and OS the difference in outcome between FLT3/ITDs and FLT3/TKDs was highly significant (P < .001). In multivariate analysis, impact of FLT3/TKDs on OS when including all mutant-positive patients was not significant, but patients with high-level mutations (more than 25% mutant) had a significantly improved outcome (P = .004). The novel finding that biologically distinct activating mutations of the same gene can be associated with markedly different clinical outcomes has implications for risk stratification and therapy and is significant to the understanding of chemoresistance in AML.

scholarly journals Frequency and Prognostic Relevance ofFLT3Mutations in Saudi Acute Myeloid Leukemia Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ghaleb Elyamany ◽  
Mohammad Awad ◽  
Kamal Fadalla ◽  
Mohamed Albalawi ◽  
Mohammad Al Shahrani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Point Mutations ◽  
Kinase Domain ◽  
High Rate ◽  
Tyrosine Kinase Domain ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that plays a key role in cell survival, proliferation, and differentiation of hematopoietic stem cells. Mutations ofFLT3were first described in 1997 and account for the most frequent molecular mutations in acute myeloid leukemia (AML). AML patients withFLT3internal tandem duplication (ITD) mutations have poor cure rates the prognostic significance of point mutations; tyrosine kinase domain (TKD) is still unclear. We analyzed the frequency ofFLT3mutations (ITD and D835) in patients with AML at diagnosis; no sufficient data currently exist regardingFLT3mutations in Saudi AML patients. This study was aimed at evaluating the frequency ofFLT3mutations in patients with AML and its significance for prognosis. The frequency ofFLT3mutations in our study (18.56%) was lower than many of the reported studies,FLT3-ITD mutations were observed in 14.4%, andFLT3-TKD in 4.1%, of 97 newly diagnosed AML patients (82 adult and 15 pediatric). Our data show significant increase ofFLT3mutations in male more than female (13 male, 5 female). Our results support the view thatFLT3-ITD mutation has strong prognostic factor in AML patients and is associated with high rate of relapse, and high leucocytes and blast count at diagnosis and relapse.

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