Successful treatment with gilteritinib for initially FMS‐like tyrosine kinase 3 gene internal tandem duplications‐positive elderly refractory acute myeloid leukemia that changed into FMS‐like tyrosine kinase 3 gene tyrosine kinase domain‐positive after cord blood transplantation

2019 ◽  
Vol 19 (10) ◽  
pp. 1063-1064 ◽  
Author(s):  
Daigo Akahane ◽  
Mitsuru Moriyama ◽  
Seiichiro Yoshizawa ◽  
Seiichiro Katagiri ◽  
Hiroaki Fujimoto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Cord Blood Transplantation ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Blood Transplantation ◽  
Refractory Acute Myeloid Leukemia ◽  
Tandem Duplications ◽  
Acute Myeloid

scholarly journals Cord Blood Transplantation for Primary Refractory Acute Myeloid Leukemia

2014 ◽  
Vol 20 (2) ◽  
pp. S154-S155
Author(s):  
Kosei Kageyama ◽  
Hisashi Yamamoto ◽  
Daisuke Kaji ◽  
Hikari Ota ◽  
Kazuya Ishiwata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Myeloid Leukemia ◽  
Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3-tyrosine kinase domain mutations

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2142-2149 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Kinase Domain Mutations ◽  
Acute Myeloid

scholarly journals Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

2018 ◽  
Vol 19 (10) ◽  
pp. 3198 ◽  
Author(s):  
Dilana Staudt ◽  
Heather Murray ◽  
Tabitha McLachlan ◽  
Frank Alvaro ◽  
Anoop Enjeti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Driver Mutations ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Therapeutic Approaches ◽  
Acute Myeloid

The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients

2020 ◽  
Vol 26 (5) ◽  
pp. 1200-1212
Author(s):  
Daniel R Reed ◽  
Jeremy M Sen ◽  
Eric J Pierce ◽  
Ramey Z Elsarrag ◽  
Michael K Keng
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Driver Mutations ◽  
Tyrosine Kinase Domain ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain

Blood ◽  
2005 ◽  
Vol 107 (1) ◽  
pp. 293-300 ◽  
Author(s):  
Florian Heidel ◽  
Fian K. Solem ◽  
Frank Breitenbuecher ◽  
Daniel B. Lipka ◽  
Stefan Kasper ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Clinical Resistance ◽  
Acute Myeloid

scholarly journals Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Juanjuan Zhao ◽  
Yongping Song ◽  
Delong Liu
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Salvage Chemotherapy ◽  
Tyrosine Kinase Domain ◽  
Dual Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

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