Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes

Virginia M. Klimek, Sophia Fircanis, Peter Maslak, Ilhem Guernah, Michael Baum, Nian Wu, Katherine Panageas, John J. Wright, Pier Paolo Pandolfi, Stephen D Nimer

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m2 i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.

Original languageEnglish
Pages (from-to)826-832
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

Fingerprint

Depsipeptides
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Pharmacokinetics
Neutropenia
Histone Deacetylase Inhibitors
Thrombocytopenia
Histones
romidepsin
Hypophosphatemia
Febrile Neutropenia
Hematopoiesis
Acetylation
Infection
Epigenomics
Nausea
Fatigue
Disease Progression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. / Klimek, Virginia M.; Fircanis, Sophia; Maslak, Peter; Guernah, Ilhem; Baum, Michael; Wu, Nian; Panageas, Katherine; Wright, John J.; Pandolfi, Pier Paolo; Nimer, Stephen D.

In: Clinical Cancer Research, Vol. 14, No. 3, 01.02.2008, p. 826-832.

Research output: Contribution to journalArticle

Klimek, Virginia M. ; Fircanis, Sophia ; Maslak, Peter ; Guernah, Ilhem ; Baum, Michael ; Wu, Nian ; Panageas, Katherine ; Wright, John J. ; Pandolfi, Pier Paolo ; Nimer, Stephen D. / Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 3. pp. 826-832.
@article{37b8f4f9524e43d68233e6821153d7d6,
title = "Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes",
abstract = "Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m2 i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.",
author = "Klimek, {Virginia M.} and Sophia Fircanis and Peter Maslak and Ilhem Guernah and Michael Baum and Nian Wu and Katherine Panageas and Wright, {John J.} and Pandolfi, {Pier Paolo} and Nimer, {Stephen D}",
year = "2008",
month = "2",
day = "1",
doi = "10.1158/1078-0432.CCR-07-0318",
language = "English",
volume = "14",
pages = "826--832",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes

AU - Klimek, Virginia M.

AU - Fircanis, Sophia

AU - Maslak, Peter

AU - Guernah, Ilhem

AU - Baum, Michael

AU - Wu, Nian

AU - Panageas, Katherine

AU - Wright, John J.

AU - Pandolfi, Pier Paolo

AU - Nimer, Stephen D

PY - 2008/2/1

Y1 - 2008/2/1

N2 - Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m2 i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.

AB - Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m2 i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.

UR - http://www.scopus.com/inward/record.url?scp=38949144400&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38949144400&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-07-0318

DO - 10.1158/1078-0432.CCR-07-0318

M3 - Article

VL - 14

SP - 826

EP - 832

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -