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

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

Research output: Contribution to journalArticle

Abstract

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with do novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701-related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease.

Original languageEnglish (US)
Pages (from-to)3669-3676
Number of pages8
JournalBlood
Volume103
Issue number10
DOIs
StatePublished - May 15 2004

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Acute Myeloid Leukemia
Refractory materials
Protein-Tyrosine Kinases
Mutation
lestaurtinib
Salvaging
Salvage Therapy
Chemotherapy
Receptor Protein-Tyrosine Kinases
Myeloid Cells
Toxicity
Bone
Leukemia
Blood
Bone Marrow
Cells
Drug Therapy
Cell Line
Survival

ASJC Scopus subject areas

  • Hematology

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

In: Blood, Vol. 103, No. 10, 15.05.2004, p. 3669-3676.

Research output: Contribution to journalArticle

Smith, B Douglas ; Levis, Mark J ; Beran, Miloslav ; Giles, Francis ; Kantarjian, Hagop ; Berg, Karin ; Murphy, Kathleen M. ; Dauses, Tianna ; Allebach, Jeffrey ; Small, Donald. / Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. In: Blood. 2004 ; Vol. 103, No. 10. pp. 3669-3676.
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