A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia.
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.
Byrd
John C
JC
Department of Internal Medicine, Division of Hematology-Oncology, Starling Loving Hall, Rm 302, The Ohio State University, Columbus, OH 43210, USA. byrd-3@medctr.osu.edu
Marcucci
Guido
G
Parthun
Mark R
MR
Xiao
Jim J
JJ
Klisovic
Rebecca B
RB
Moran
Mollie
M
Lin
Thomas S
TS
Liu
Shujun
S
Sklenar
Amy R
AR
Davis
Melanie E
ME
Lucas
David M
DM
Fischer
Beth
B
Shank
Roshini
R
Tejaswi
Sooraj L
SL
Binkley
Philip
P
Wright
John
J
Chan
Kenneth K
KK
Grever
Michael R
MR
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D015331:Cohort Studies; D047630:Depsipeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D006655:Histone Deacetylases