Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Tarver, Theodore C.; Hill, Jason E.; Rahmat, Leena T.; Perl, Alexander E.; Bahceci, Erkut; Mori, Kenichi; Smith, Catherine C.

doi:10.1182/bloodadvances.2019000919

Cited by 63 publications

(57 citation statements)

References 39 publications

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“…Similarly, in a study of 18 patients treated with crenolanib, pre- and post-treatment sequencing identified small populations of four NC mutations at baseline which were eliminated over the course of treatment (A833S, D839Y/G, N841K, Y842C) ( 64 ). In a recent in vitro study, gilteritinib was active against multiple NC mutations, including mutations like N676, which are associated with resistance to midostaurin and quizartinib ( 149 ). Finally, in a recent case series, two patients with non- FLT3- ITD or D835 AML were found to have JM FLT3-V592G and KD FLT3-N676K mutations, both of which clinically responded to sorafenib ( 146 ).…”

Section: Ongoing Questions and Controversiesmentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

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Section: Ongoing Questions and Controversiesmentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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“…D. FLT3 activity is sustained with mutations in N701K and F691L. Ba/F3 cells harboring FLT3 ITD , FLT3 ITD+F701K , and FLT3 ITD+F691L were treated with gilteritinib (0 – 400 nM) for 90 minutes and lysed for immunoblot analysis 4, 6 .…”

Section: Resultsmentioning

confidence: 99%

“…Another set of mutations in the tyrosine kinase domain (TKD) of FLT3 occur in 5-10% of AML patients. In contrast to FLT3-ITD, FLT3 TKD mutations result in less activation of FLT3 and do not increase the risk of relapse 3 [4][5][6] . These mutations occur frequently at the activation loop residue D835 and less commonly at F691 which represents the "gatekeeper" position in FLT3 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Resistance to gilteritinib most commonly occurs through acquisition/expansion of NRAS mutations, however a minority of patients with F691L gatekeeper mutations were also identified 8 . To search for additional resistance mutations to gilteritinib, Tarver et al used a well-established ENU mutagenesis assay and identified Y693C/N and G697S as mutations that confer resistance in vitro 6 . These mutations appear to function similar to the gatekeeper mutation by blocking gilteritinib binding to FLT3, but have not been reported in patients.…”

Section: Introductionmentioning

confidence: 99%

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A noncanonical FLT3 gatekeeper mutation disrupts gilteritinib binding and confers resistance

Joshi

Sharzehi

Pittsenbarger

et al. 2021

Preprint

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The recent FDA approval of the FLT3 inhibitor, gilteritinib, for AML represents a major breakthrough for treatment of FLT3 mutated AML. However, patients only respond to gilteritinib for 6-7 months due to the emergence of drug resistance. Clinical resistance to gilteritinib is often associated with expansion of NRAS mutations, and less commonly via gatekeeper mutations in FLT3, with F691L being the most common. We developed an in vitro model that charts the temporal evolution of resistance to gilteritinib from early microenvironmental-mediated resistance to late intrinsic resistance mutations. Our model system accurately recapitulates the expansion of NRAS mutations and the F691L gatekeeper mutations found in AML patients. As part of this study, we also identified a novel FLT3N701K mutation that also appeared to promote resistance to gilteritinib. Using the Ba/F3 system, we demonstrate that N701K mutations effectively act like a gatekeeper mutation and block gilteritinib from binding to FLT3, thereby promoting resistance. Structural modeling of FLT3 reveals how N701K, and other reported gilteritinib resistance mutations, obstruct the gilteritinib binding pocket on FLT3. Interestingly, FLT3N701K does not block quizartinib binding, suggesting that FLT3N701K mutations are more specific for type 1 FLT3 inhibitors (gilteritinib, midostaurin, and crenolanib). Thus, our data suggests that for the FLT3N701K mutation, switching classes of FLT3 inhibitors may restore clinical response. As the use of gilteritinib expands in the clinic, this information will become critical to define clinical strategies to manage gilteritinib resistance.

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“…Data suggest that higher doses of gilteritinib above 200 mg/day may potentially overcome resistance associated with FLT3-F691L mutations. 56 It is important to note that doses of 200–300 were tolerated in the phase I/II trial; however, a dose of 120 mg/day was assessed in the randomized phase III trial and is currently the FDA approved dose.…”

Section: Mechanism Of Resistancementioning

confidence: 99%

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

Chew

Mackey

Jabbour

2020

Therapeutic Advances in Hematology

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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.

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Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Cited by 63 publications

References 39 publications

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

A noncanonical FLT3 gatekeeper mutation disrupts gilteritinib binding and confers resistance

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

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