Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia

Smith, B. Douglas; Levis, Mark J.; Beran, Miloslav; Giles, Francis J.; Kantarjian, Hagop M.; Berg, Karin D.; Murphy, Kathleen M.; Dauses, Tianna; Allebach, Jeffrey; Small, Donald

doi:10.1182/blood-2003-11-3775

Cited by 583 publications

(472 citation statements)

References 33 publications

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“…There are no reports of significant cardiotoxicity in phase I-II trials of lestaurtinib in patients with acute myeloid leukaemia and activating FLT3 mutations 88 , but prospective monitoring of cardiac function has not been carried out.…”

Section: Sorafenibmentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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Section: Sorafenibmentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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“…2 It was shown that FLT3 inhibitors were only marginally effective in unselected AML, whereas responses were more frequently observed in patients harboring mutant FLT3. [8][9][10] For example, in the first phase I trial, testing the FLT3 inhibitor sorafenib (Nexavar, formerly BAY 43-9006) in AML only FLT3-ITD-positive (FLT3-ITD), but not FLT3-ITD-negative AML patients responded. 11 Three subsequent phase I studies underscored this evidence by demonstrating consistent activity of sorafenib in relapsed and refractory FLT3-ITD AML, while primary resistance was frequently seen in AML expressing the wild-type form of FLT3.…”

Section: Introductionmentioning

confidence: 99%

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

et al. 2012

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Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P ¼ 0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

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“…Relapsed/refractory AML patients showed transient clinical responses to CEP-701 in early clinical trials (Smith et al, 2004). Transient clinical responses were also observed in a Phase II trial for older AML patients not eligible for intensive chemotherapy (Knapper et al, 2006).…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 97%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia

Abstract: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Target

Cited by 583 publications

References 33 publications

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

Drug resistance in mutant FLT3-positive AML

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