Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia.
OBJECTIVE
Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML.


METHODS
Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m(2)/d on days 1, 8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points.


RESULTS
Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a >50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P=0.005), p15 (P=0.01), and p14 (P<0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant.


CONCLUSIONS
Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.
Odenike
Olatoyosi M
OM
Medicine Studies, University of Chicago, Chicago, Illinois, USA. todenike@medicine.bsd.uchicago.edu
Alkan
Serhan
S
Sher
Dorie
D
Godwin
John E
JE
Huo
Dezheng
D
Brandt
Stephen J
SJ
Green
Margaret
M
Xie
Jingping
J
Zhang
Yanming
Y
Vesole
David H
DH
Stiff
Patrick
P
Wright
John
J
Larson
Richard A
RA
Stock
Wendy
W
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002869:Chromosome Aberrations; D015331:Cohort Studies; D050660:Core Binding Factors / Q000378:metabolism*; D047630:Depsipeptides / Q000009:adverse effects / Q000627:therapeutic use*; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000009:adverse effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
D000903:Antibiotics, Antineoplastic; D050660:Core Binding Factors; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D006655:Histone Deacetylases