scholarly journals Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation

2020 ◽  
Vol 11 ◽  
pp. 204062072093061
Author(s):  
Serena Chew ◽  
Melissa C. Mackey ◽  
Elias Jabbour
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Clonal Evolution ◽  
Response To Therapy ◽  
Activating Mutations ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a malignancy of uncontrolled proliferation of immature myeloid blasts characterized by clonal evolution and genetic heterogeneity. FMS-like tyrosine kinase 3 (FLT3) mutations occur in up to a third of AML cases and are associated with highly proliferative disease, shorter duration of remission, and increased rates of disease relapse. The known impact of activating mutations in FLT3 in AML on disease pathogenesis, prognosis, and response to therapy has led to the development of tyrosine kinase inhibitors targeting FLT3. Gilteritinib is a potent, second generation inhibitor of both FLT3 and AXL, designed to address the limitations of other FLT3 inhibitors, particularly in targeting mechanisms of resistance to other drugs. In this review, we present comprehensive data on recent and ongoing studies evaluating the role of gilteritinib in the relapsed and refractory FLT3 mutated AML setting.

scholarly journals Clinical Implications of Inflammation in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Acute Myeloid

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

Gilteritinib use in the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation

2020 ◽  
Author(s):  
Octavio Ballesta-López ◽  
Antonio Solana-Altabella ◽  
Juan Eduardo Megías-Vericat ◽  
David Martínez-Cuadrón ◽  
Pau Montesinos
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Salvage Chemotherapy ◽  
Mechanisms Of Resistance ◽  
Flt3 Inhibitor ◽  
Refractory Acute Myeloid Leukemia ◽  
Dose Reductions ◽  
Acute Myeloid

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is dismal with salvage standard approaches, and mutations of FMS-like tyrosine kinase 3 ( FLT3) gene, occurring in around 30% of AML patients may confer even poorer outcomes. Several targeted tyrosine kinase inhibitors have been developed to improve FLT3-mutated AML patient´s survival. Gilteritinib, a highly specific second-generation class I oral FLT3 inhibitor, has demonstrated superiority to salvage chemotherapy (SC) in R/R FLT3 mutated AML based on significantly longer OS in the gilteritinib arm than in the SC arm. Gilteritinib is generally well tolerated, but some clinically relevant adverse events should be monitored, especially myelosuppression, QTc prolongation and differentiation syndrome, usually manageable (dose reductions, interruption or discontinuation) and reversible. We discuss clinical development, efficacy, safety and mechanisms of resistance of gilteritinib in the treatment of R/R patients with FLT3 mutated AML.

Acquired BCR-ABL1 fusion and IDH1 clonal evolution following BCL2 inhibitor treatment in refractory acute myeloid leukemia

2021 ◽  
Vol 100 ◽  
pp. 106494
Author(s):  
Diego Adrianzen-Herrera ◽  
Ximena Jordan-Bruno ◽  
Katherine A. Devitt ◽  
Joanna L. Conant ◽  
Juli-Anne Gardner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Refractory Acute Myeloid Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

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
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