SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes

Francis J. Giles, Alison T. Stopeck, Lewis R. Silverman, Jeffrey E. Lancet, Maureen A. Cooper, Alison L. Hannah, Julie M. Cherrington, Anne Marie O'Farrell, Helene A. Yuen, Sharianne G. Louie, Weiru Hong, Jorge E. Cortes, Srdan Verstovsek, Maher Albitar, Susan M. O'Brien, Hagop M. Kantarjian, Judith E. Karp

Research output: Contribution to journalArticle

Abstract

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.

Original languageEnglish (US)
Pages (from-to)795-801
Number of pages7
JournalBlood
Volume102
Issue number3
DOIs
StatePublished - Aug 1 2003

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Myelodysplastic Syndromes
Receptor Protein-Tyrosine Kinases
Acute Myeloid Leukemia
Refractory materials
Molecules
Vascular Endothelial Growth Factor Receptor
Vascular Endothelial Growth Factor A
Toxicity
Bone
Vascular Endothelial Growth Factor Receptor-2
Drug Compounding
Semaxinib
Fatigue of materials
Drug-Related Side Effects and Adverse Reactions
Dyspnea
Fatigue
Headache
Pharmaceutical Preparations
Bone Marrow
Bone and Bones

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. / Giles, Francis J.; Stopeck, Alison T.; Silverman, Lewis R.; Lancet, Jeffrey E.; Cooper, Maureen A.; Hannah, Alison L.; Cherrington, Julie M.; O'Farrell, Anne Marie; Yuen, Helene A.; Louie, Sharianne G.; Hong, Weiru; Cortes, Jorge E.; Verstovsek, Srdan; Albitar, Maher; O'Brien, Susan M.; Kantarjian, Hagop M.; Karp, Judith E.

In: Blood, Vol. 102, No. 3, 01.08.2003, p. 795-801.

Research output: Contribution to journalArticle

Giles, FJ, Stopeck, AT, Silverman, LR, Lancet, JE, Cooper, MA, Hannah, AL, Cherrington, JM, O'Farrell, AM, Yuen, HA, Louie, SG, Hong, W, Cortes, JE, Verstovsek, S, Albitar, M, O'Brien, SM, Kantarjian, HM & Karp, JE 2003, 'SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes', Blood, vol. 102, no. 3, pp. 795-801. https://doi.org/10.1182/blood-2002-10-3023
Giles, Francis J. ; Stopeck, Alison T. ; Silverman, Lewis R. ; Lancet, Jeffrey E. ; Cooper, Maureen A. ; Hannah, Alison L. ; Cherrington, Julie M. ; O'Farrell, Anne Marie ; Yuen, Helene A. ; Louie, Sharianne G. ; Hong, Weiru ; Cortes, Jorge E. ; Verstovsek, Srdan ; Albitar, Maher ; O'Brien, Susan M. ; Kantarjian, Hagop M. ; Karp, Judith E. / SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. In: Blood. 2003 ; Vol. 102, No. 3. pp. 795-801.
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abstract = "Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30{\%}] primary refractory, 23 [70{\%}] relapsed; 22 MDS: 15 [68{\%}] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14{\%}), infusion-related reactions (11{\%}), dyspnea (14{\%}), fatigue (7{\%}), thrombotic episodes (7{\%}), bone pain (5{\%}), and gastrointestinal disturbance (4{\%}). There were 11 patients (20{\%}) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5{\%}) who achieved partial responses; and 1 (2{\%}) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.",
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AU - Lancet, Jeffrey E.

AU - Cooper, Maureen A.

AU - Hannah, Alison L.

AU - Cherrington, Julie M.

AU - O'Farrell, Anne Marie

AU - Yuen, Helene A.

AU - Louie, Sharianne G.

AU - Hong, Weiru

AU - Cortes, Jorge E.

AU - Verstovsek, Srdan

AU - Albitar, Maher

AU - O'Brien, Susan M.

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N2 - Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.

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