A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia

John C. Byrd, Guido Marcucci, Mark R. Parthun, Jim J. Xiao, Rebecca B. Klisovic, Mollie Moran, Thomas S. Lin, Shujun Liu, Amy R. Sklenar, Melanie E. Davis, David M. Lucas, Beth Fischer, Roshini Shank, Sooraj Lakshmi Tejaswi, Philip Binkley, John Wright, Kenneth K. Chan, Michael R. Grever

Research output: Contribution to journalArticle

357 Citations (Scopus)

Abstract

Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m 2 depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules.

Original languageEnglish (US)
Pages (from-to)959-967
Number of pages9
JournalBlood
Volume105
Issue number3
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

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Depsipeptides
Pharmacodynamics
B-Cell Chronic Lymphocytic Leukemia
Acute Myeloid Leukemia
Acetylation
Histone Deacetylases
Histones
Toxicity
Appointments and Schedules
Histone Deacetylase Inhibitors
National Cancer Institute (U.S.)
Nausea
Fatigue
Proteins
romidepsin
Fatigue of materials
Apoptosis
Antigens
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

Byrd, J. C., Marcucci, G., Parthun, M. R., Xiao, J. J., Klisovic, R. B., Moran, M., ... Grever, M. R. (2005). A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood, 105(3), 959-967. https://doi.org/10.1182/blood-2004-05-1693

A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. / Byrd, John C.; Marcucci, Guido; Parthun, Mark R.; Xiao, Jim J.; Klisovic, Rebecca B.; Moran, Mollie; Lin, Thomas S.; Liu, Shujun; Sklenar, Amy R.; Davis, Melanie E.; Lucas, David M.; Fischer, Beth; Shank, Roshini; Tejaswi, Sooraj Lakshmi; Binkley, Philip; Wright, John; Chan, Kenneth K.; Grever, Michael R.

In: Blood, Vol. 105, No. 3, 01.02.2005, p. 959-967.

Research output: Contribution to journalArticle

Byrd, JC, Marcucci, G, Parthun, MR, Xiao, JJ, Klisovic, RB, Moran, M, Lin, TS, Liu, S, Sklenar, AR, Davis, ME, Lucas, DM, Fischer, B, Shank, R, Tejaswi, SL, Binkley, P, Wright, J, Chan, KK & Grever, MR 2005, 'A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia', Blood, vol. 105, no. 3, pp. 959-967. https://doi.org/10.1182/blood-2004-05-1693
Byrd, John C. ; Marcucci, Guido ; Parthun, Mark R. ; Xiao, Jim J. ; Klisovic, Rebecca B. ; Moran, Mollie ; Lin, Thomas S. ; Liu, Shujun ; Sklenar, Amy R. ; Davis, Melanie E. ; Lucas, David M. ; Fischer, Beth ; Shank, Roshini ; Tejaswi, Sooraj Lakshmi ; Binkley, Philip ; Wright, John ; Chan, Kenneth K. ; Grever, Michael R. / A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. In: Blood. 2005 ; Vol. 105, No. 3. pp. 959-967.
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