scholarly journals Maintenance therapy for FLT3-ITD-mutated acute myeloid leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Andreas Burchert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Hematopoietic Stem ◽  
Therapeutic Concept ◽  
Treatment Paradigm ◽  
Acute Myeloid

FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. This review describes key milestones in the clinical development of different FLT3-specific TKI with a particular focus on FLT3-TKI maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT). Recent evidence from randomized trials using sorafenib in FLT3-ITD mutated AML provided a proof of concept that targeted post-HCT maintenance therapy could become a new treatment paradigm in AML.

scholarly journals An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

2012 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Tiziana Grafone ◽  
Michela Palmisano ◽  
Chiara Nicci ◽  
Sergio Storti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Molecular Therapy ◽  
Tyrosine Kinase Receptor ◽  
Hematopoietic Stem ◽  
Downstream Signaling ◽  
Proliferation And Differentiation ◽  
Acute Myeloid

Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The <em>FLT3</em> gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.

FLT3 inhibitors in acute myeloid leukemia: Current and future

2018 ◽  
Vol 25 (1) ◽  
pp. 163-171 ◽  
Author(s):  
Christan M Thomas ◽  
Peter Campbell
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Significant Toxicity ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is responsible for the proliferation and survival of hematopoietic stem cells in acute myeloid leukemia. Although patients with FLT3 mutations have similar rates of remission following induction chemotherapy, relapse rates are significantly higher and patients with FLT3 mutations have significantly worse outcomes for overall survival and disease-free survival. Early FLT3 inhibitors, such as sorafenib, were non-selective and inhibited several tyrosine kinase receptors resulting in significant toxicity. The treatment of FLT3-positive acute myeloid leukemia has advanced recently with the development of a several FLT3-targeting agents that are either approved or in development. Midostaurin represents the first FDA-approved treatment targeted against FLT3, and there are several promising agents currently undergoing clinical trials. Although certain mutations confer resistance to earlier generation FLT3-targeted tyrosine kinase inhibitors, newer agents show activity in the presence of these mutations.

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

2019 ◽  
Vol 15 (34) ◽  
pp. 3885-3894 ◽  
Author(s):  
Shilpa Paul ◽  
Adam J DiPippo ◽  
Farhad Ravandi ◽  
Tapan M Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Internal Tandem Duplication ◽  
Acute Myeloid

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

scholarly journals Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

2017 ◽  
Vol 4 (6) ◽  
pp. 48-48 ◽  
Author(s):  
Yun Chen ◽  
Yihang Pan ◽  
Yao Guo ◽  
Wanke Zhao ◽  
Wanting Tina Ho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Acute Myeloid

scholarly journals MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
María Luz Morales ◽  
Alicia Arenas ◽  
Alejandra Ortiz-Ruiz ◽  
Alejandra Leivas ◽  
Inmaculada Rapado ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Resistance Pathway ◽  
Acute Myeloid

AbstractFMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

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