The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

Testa, Ugo

doi:10.1155/2013/275760

Cited by 14 publications

(12 citation statements)

References 92 publications

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“…However, it is unclear if the benefit of midostaurin in these patients is related to inhibition of FLT3 activity or other actions of the drug. Given that FLT3‐ITD is a driver mutation in AML, it is possible that an agent such as quizartinib that has greater potency and selectivity toward FLT3‐ITD may have a more pronounced effect on the clinical course of disease. The phase 3 QuANTUM‐First trial (NCT02668653) is currently evaluating quizartinib 40 mg vs placebo in combination with SOC induction/consolidation chemotherapy and as maintenance therapy in patients with FLT3‐ITD mutated ndAML.…”

Section: Discussionmentioning

confidence: 99%

“…One of the most common molecular alterations observed in patients with ndAML is internal tandem duplication (ITD) mutation of the FLT3 receptor, a driver mutation for disease progression that occurs in approximately 25% of cases . FLT3‐ITD mutation identifies a high‐risk population of AML patients with an increased risk of early relapse, increased mortality following SOC chemotherapy, and a high need for improved treatment options .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

Altman¹,

Foran

Pratz

et al. 2017

American J Hematol

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Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy.Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n 5 6), 60 mg/d for 14 days (DL2; n 5 7), and 40 mg/d for 14 days (DL-1; n 5 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade 1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients. | I N TR ODU C TI ONOne of the most common molecular alterations observed in patients with ndAML is internal tandem duplication (ITD) mutation of the FLT3 receptor, a driver mutation for disease progression that occurs in approximately 25% of cases. 1-6 FLT3-ITD mutation identifies a high-risk population of AML patients with an increased risk of early relapse, increased mortality following SOC chemotherapy, and a high need for improved treatment wileyonlinelibrary.com/journal/ajh

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

Altman¹,

Foran

Pratz

et al. 2017

American J Hematol

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“…FMS-like receptor tyrosine kinase 3 (FLT3), a member of the class III tyrosine kinase family, is expressed in some normal hematopoietic cell types [1,2] and plays an important role in the pathogenesis of acute myeloid leukemia (AML) [3] . FLT3 mutations are among the most common abnormalities in acute myeloid leukemia, affecting more than one third of all AML patients [4] .…”

Section: Introductionmentioning

confidence: 99%

The antitumor compound triazoloacridinone C-1305 inhibits FLT3 kinase activity and potentiates apoptosis in mutant FLT3-ITD leukemia cells

et al. 2015

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Aim: FMS-like receptor tyrosine kinase (FLT3) is expressed in some normal hematopoietic cell types and plays an important role in the pathogenesis of acute myeloid leukemia (AML). In this study, we examined the effects of triazoloacridinone C-1305, an antitumor compound, on AML cells with different FLT3 status in vitro. Methods: A panel of human leukemic cell lines with different FLT3 status was used, including FLT3 internal tandem duplication mutations (FLT3-ITD, MV-4-11), wild-type FLT3 (RS-4-11) and null-FLT3 (U937) cells. Cell proliferation was estimated using MTT assays, and apoptosis was studied with flow cytometry and fluorescence microscopy. FLT3 kinase activity (phosphorylation of FLT3 at Tyr591) was determined with ELISA and Western blotting. FLT3 downstream signaling proteins involving AKT, MAPK and STAT5 were examined by Western blotting. RNA silencing was used to decrease the endogenous FLT3. Results: The mutant FLT3-ITD cells were more sensitive to C-1305 than the wild-type FLT3 and null-FLT3 cells (the IC 50 values measured at 24 h were 1.2±0.17, 2.0±09, 7.6±1.6 µmol/L, respectively). C-1305 (1-10 µmol/L) dose-dependently inhibited the kinase activity of FLT3, which was more pronounced in the mutant FLT3-ITD cells than in the wild-type FLT3 cells. Furthermore, C-1305 dose-dependently decreased the phosphorylation of STAT5 and MAPK and the inhibitory phosphorylation of Bad, and induced timeand dose-dependent apoptosis in the 3 cell lines with the null-FLT3 cells being the least susceptible to C-1305-induced apoptosis. Knockdown of FLT3 with siRNA significantly decreased C-1305-induced cytotoxicity in the mutant FLT3-ITD cells. Conclusion: C-1305 induces apoptosis in FLT3-ITD-expressing human leukemia cells in vitro, suggesting that mutated FLT3 kinase can be a new target for C-1305, and C-1305 may be a drug candidate for the therapeutic intervention in FLT3-associated AML.

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“…These are analogous to the patterns of mutation seen with driver oncogenes such as FLT3 in acute myeloid leukemia (LAML; ref. 104), and may indicate a specific driver contribution in these cancer types.…”

Section: Kinome Disease Associationmentioning

confidence: 99%

New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome

et al. 2018

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The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. .

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The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

Cited by 14 publications

References 92 publications

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

The antitumor compound triazoloacridinone C-1305 inhibits FLT3 kinase activity and potentiates apoptosis in mutant FLT3-ITD leukemia cells

New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome

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