ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML).

Mori, Masamichi; Kaneko, Naoki; Ueno, Yoshio; Tanaka, Ray; Cho, Kathy; Saito, Rika; Kondoh, Yutaka; Shimada, Ichio; Kuromitsu, Sadao

doi:10.1200/jco.2014.32.15_suppl.7070

Cited by 20 publications

(19 citation statements)

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“…Newer inhibitors are being investigated that have shown to target both ITD and TKD mutations, including crenolanib [83, 84], and gilteritinib (ASP2215) but large studies of outcomes of patients, and resistance in these patients, are yet to be described [85, 86]. …”

Section: Biologic Mechanisms For Flt3 Itd Genomic Instabilitymentioning

confidence: 99%

Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

Rebechi

Pratz

2017

Leukemia & Lymphoma

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Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways. The role of genomic instability in the pathogenesis of FLT3 ITD AML warrants further examination as it offers potential therapeutic targets.

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Section: Biologic Mechanisms For Flt3 Itd Genomic Instabilitymentioning

confidence: 99%

Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

Rebechi

Pratz

2017

Leukemia & Lymphoma

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“…Gilteritinib (formerly known as ASP2215) is another orally bioavailable RTK that has demonstrated promising antileukemia activity against nonclinical AML models harboring FLT3-ITD, FLT3-D835 mutations or both [87]. Gilteritinib potently inhibits multiple tyrosine kinases, primarily FLT3, AXL, and anaplastic lymphoma kinase (ALK or CD246).…”

Section: Gilteritinibmentioning

confidence: 99%

Management of Relapsed/Refractory Acute Myeloid Leukemia in the Elderly: Current Strategies and Developments

Bryan

Jabbour²

2015

Drugs Aging

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Elderly patients with acute myeloid leukemia (AML) who are refractory to or relapse following frontline treatment constitute a poor-risk group with a poor long-term outcome. Host-related factors and unfavorable disease-related features contribute to early treatment failures following frontline therapy, thus making attainment of remission and long-term survival with salvage therapy particularly challenging for elderly patients. Currently, no optimal salvage strategy exists for responding patients, and allogeneic hematopoietic stem cell transplant is the only curative option in this setting; however, the vast majority of elderly patients are not candidates for this procedure due to poor functional status secondary to age and age-related comorbidities. Furthermore, the lack of effective salvage programs available for elderly patients with recurrent AML underscores the need for therapies that consistently yield durable remissions or durable control of their disease. The purpose of this review was to highlight the currently available strategies, as well as future strategies under development, for treating older patients with recurrent AML.

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“…Other FLT3 inhibitors undergoing frontline evaluation include crenolanib, a type 1 FLT3 inhibitor active against both FLT3 ‐ITD and FLT3 ‐TKD mutant AML and gilteritinib, a type 1 FLT3/AXL inhibitor . Phase 1b/2 studies have been conducted and show promising activity and tolerability for either crenolanib (NCT02283177) or gilteritinib (NCT02236013) in combination with chemotherapy in patients with FLT3 mutant AML.…”

Section: New Frontiers In Frontline Aml Therapy In Patients Fit For Imentioning

confidence: 99%

New drugs creating new challenges in acute myeloid leukemia

Tiong

Wei

2019

Genes Chromosomes & Cancer

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The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively; CPX‐351 (liposomal cytarabine and daunorubicin) for therapy‐related AML and AML with myelodysplasia‐related changes; gemtuzumab ozogamicin (anti‐CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33‐positive AML; enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively. Novel therapies have also emerged for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. These include venetoclax (BCL‐2 inhibitor) in combination with hypomethylating agents (azacitidine or decitabine) or low‐dose cytarabine (LDAC), and glasdegib (sonic hedgehog pathway inhibitor) in combination with LDAC. This flurry of new drug approvals has markedly altered the treatment landscape in AML and provided new opportunities, as well as new challenges for treating clinicians. This review will focus on how these drugs might shape clinical practice and the hurdles likely to be faced by new therapies seeking entry into this dynamic and rapidly changing therapeutic landscape.

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ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML).

Cited by 20 publications

References 0 publications

Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

Management of Relapsed/Refractory Acute Myeloid Leukemia in the Elderly: Current Strategies and Developments

New drugs creating new challenges in acute myeloid leukemia

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