ASP2215 in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia with
            <i>FLT3</i>
            Mutation: Background and Design of the ADMIRAL Trial

Gorcea, Claudia M; Burthem, John; Tholouli, Eleni

doi:10.2217/fon-2017-0582

Cited by 24 publications

(15 citation statements)

References 36 publications

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“…the largest population of AML patients), and those with other comorbidities, 7+3 chemotherapy is not well tolerated due to its extensive toxicities and severe side effects (5). Gilteritinib was approved by the US FDA in November 2018 for use in adult patients with relapsed or refractory FLT3-mutated AML, following the ADMIRAL trial () (6). As such, treatment options for FLT3-mutated AML are beginning to exist, but carry with them certain limitations -particularly in relation to monotherapy, with efficacious but short-lived responses.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Zhao

Qiao

et al. 2019

Clinical Cancer Research

125

105

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Purpose: To investigate the efficacy of the combination of the FLT3 inhibitors midostaurin or gilteritinib with the Bcl-2 inhibitor venetoclax in FLT3-ITD acute myeloid leukemia (AML) and the underlying molecular mechanism. Experimental Design: Using both FLT3-ITD cell lines and primary patient samples, annexin V-FITC/propidium iodide staining and flow cytometry analysis were used to quantify cell death induced by midostaurin or gilteritinib, alone or in combination with venetoclax. Western blot analysis was performed to assess changes in protein expression levels of members of the JAK/ STAT, MAPK/ERK, and PI3K/AKT pathways, and members of the Bcl-2 family of proteins. The MV4-11-derived xenograft mouse model was used to assess in vivo efficacy of the combination of gilteritinib and venetoclax. Lentiviral overexpression of Mcl-1 was used to confirm its role in cell

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Section: Introductionmentioning

confidence: 99%

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Zhao

Qiao

et al. 2019

Clinical Cancer Research

125

105

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“…Gilteritinib is a selective FLT3 inhibitor that inhibits both FLT3-ITD and FLT3-TKD mutations, and is classified as an ATP-competitive type I inhibitor [17]. Based on a phase 3 clinical trial, gilteritinib was recently approved by the Pharmaceuticals and Medical Devices Agency and FDA as monotherapy for patients with relapsed/refractory FLT3 -mutated AML [18].…”

Section: Introductionmentioning

confidence: 99%

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

et al. 2019

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Therapeutic effects of FLT3 inhibitors have been reported in acute myeloid leukemia (AML) with constitutively activating FLT3 mutations, including internal tandem duplication (ITD) and point mutation, which are found in approximately one-third of AML patients. One of the critical issues of treatment with FLT3 inhibitors in FLT3-mutated AML is drug resistance. FLT3 ligand (FL) represents a mechanism of resistance to FLT3 inhibitors, including quizartinib, midostaurin, and sorafenib, in AML cells harboring both wild-type and mutant FLT3 (FLT3wt/FLT3mut). Here, we investigated the effect of FL on the efficacy of gilteritinib, a FLT3 inhibitor, in AML-derived cells in vitro and in mice. In contrast to other FLT3 inhibitors, FL stimulation had little effect on growth inhibition or apoptosis induction by gilteritinib. The antitumor activity of gilteritinib was also comparable between xenograft mouse models injected with FL-expressing and mock MOLM-13 cells. In the FLT3 signaling analyses, gilteritinib inhibited FLT3wt and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells. Co-crystal structure analysis showed that gilteritinib bound to the ATP-binding pocket of FLT3. These results suggest that gilteritinib has therapeutic potential in FLT3-mutated AML patients with FL overexpression.

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“…Based on an international randomized controlled study showing that the combination of Midostaurin and chemotherapy improved the outcome of adult AML patients, the drug recently became FDA-approved for therapy of de novo FLT3-mutated AML (141). Very recently, Gliternitinib was also FDA-approved for relapsed/refractory AML with FLT3 mutations based on results from the ADMIRAL trial (142). Several FLT3 inhibitors have been explored in small clinical trials in pediatric AML patients, and partial or complete responses were reported not only in KMT2A-rearranged ALL (Midostaurin, Lestauritinib), but also in refractory/relapse AML (Sorafenib) (143).…”

Section: Molecular Targeting Of Pediatric Amlmentioning

confidence: 99%

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Mercher

Schwaller

2019

Front. Pediatr.

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This review aims to provide an overview of the current knowledge of the genetic lesions driving pediatric acute myeloid leukemia (AML), emerging biological concepts, and strategies for therapeutic intervention. Hereby, we focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, NUP98, or CBFA2T3, respectively. Functional studies were able to demonstrate cooperation with signaling mutations leading to constitutive activation of FLT3 or the RAS signal transduction pathways. We discuss the issues faced to faithfully model pediatric acute leukemia in mice. Emerging experimental evidence suggests that the disease phenotype is dependent on the appropriate expression and activity of the driver fusion oncogenes during a particular window of opportunity during fetal development. We also highlight biochemical studies that deciphered some molecular mechanisms of malignant transformation by KMT2A, NUP98, and CBFA2T3 fusions, which, in some instances, allowed the development of small molecules with potent anti-leukemic activities in preclinical models (e.g., inhibitors of the KMT2A–MENIN interaction). Finally, we discuss other potential therapeutic strategies that not only target driver fusion-controlled signals but also interfere with the transformed cell state either by exploiting the primed apoptosis or vulnerable metabolic states or by increasing tumor cell recognition and elimination by the immune system.

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ASP2215 in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia with FLT3 Mutation: Background and Design of the ADMIRAL Trial

Cited by 24 publications

References 36 publications

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

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