Which FLT3 Inhibitor for Treatment of AML?

Senapati, Jayastu; Kadia, Tapan M.

doi:10.1007/s11864-022-00952-6

Cited by 9 publications

(12 citation statements)

References 130 publications

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“… 23 , 30 Apart from this broad classification, both first and next-generation inhibitors could be either type I or type II inhibitors in relation to their effectiveness against both FLT3-ITD and TKD mutations or only FLT3-ITD mutation, respectively. 23 , 30 , 83 Type I inhibitors can bind to both active and inactive conformations of the FLT3 receptor since they bind to the FLT3 gatekeeper domain or the ATP binding pocket. Type II inhibitors bind adjacent to ATP binding domain located in the hydrophobic region when the receptor is in its inactive conformation.…”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

“… 84 First-generation inhibitors include midostaurin and sorafenib, which are also type I and type II inhibitors, respectively. 23 , 30 , 83 , 84 …”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

“…Clinical decisions on a specific FLT3i for a specific group of patients such as how to choose a proper concentration of FLT3i in combination approaches, and when to use FLT3i (as a frontline or maintenance therapy), before or allo-SCT should be carefully considered based on the presence of simultaneous myeloid neoplasm-related mutations, type of FLT3 mutation, FLT3-ITD insertion size and position, the use of prior FLT3i, the toxicity profile of FLT3i, patients’ age and overall health condition and eligibility for allo-SCT. 83 …”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

“…Type II inhibitors bind adjacent to ATP binding domain located in the hydrophobic region when the receptor is in its inactive conformation. 83 In this review, we have specifically focused on the FLT3is approved for the clinical settings (Table 1) and we will summarize the clinical trials of these FLT3is involved in novel combination studies (Table 2). First-Generation FLT3 Inhibitors…”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

“…84 First-generation inhibitors include midostaurin and sorafenib, which are also type I and type II inhibitors, respectively. 23,30,83,84 Midostaurin is active against both FLT3-ITD and TKD mutations and showed limited and transient activity in early clinical phase trials when used alone. In a clinical setting including relapsed/refractory (R/R) FLT3-mutated AML patients, midostaurin induced a 50% reduction in peripheral and bone marrow blasts.…”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

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Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

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Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

“… 84 First-generation inhibitors include midostaurin and sorafenib, which are also type I and type II inhibitors, respectively. 23 , 30 , 83 , 84 …”

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

Section: Clinically Approved Flt3 Inhibitors In Therapymentioning

confidence: 99%

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Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Tecik,

Adan

2024

Curr. Treat. Options in Oncol.

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Opinion statementThe internal tandem duplication (ITD) mutation of the FMS-like receptor tyrosine kinase 3 (FLT3-ITD) is the most common mutation observed in approximately 30% of acute myeloid leukemia (AML) patients. It represents poor prognosis due to continuous activation of downstream growth-promoting signaling pathways such as STAT5 and PI3K/AKT. Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. However, patients possess generally poor remission rates and acquired resistance when FLT3I used alone. Various factors in patients could cause these adverse effects including altered epigenetic regulation, causing mainly abnormal gene expression patterns. Epigenetic modifications are required for hematopoietic stem cell (HSC) self-renewal and differentiation; however, critical driver mutations have been identified in genes controlling DNA methylation (such as DNMT3A, TET2, IDH1/2). These regulators cause leukemia pathogenesis and affect disease diagnosis and prognosis when they co-occur with FLT3-ITD mutation. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I’s activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients’ mutational status in terms of FLT3 and DNA methlome regulators.

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Targeted therapy

De¹

2023

Medicines for Cancer

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Which FLT3 Inhibitor for Treatment of AML?

Cited by 9 publications

References 130 publications

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Targeted therapy

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